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Vogt-Koyanagi-Harada disease: Novel insights into pathophysiology, diagnosis and treatment
Accepted Manuscript Vogt-Koyanagi-Harada disease: Novel insights into pathophysiology, diagnosis and treatment Liping Du, Aize Kijlstra, Peizeng Yang, MD, PhD PII:
S1350-9462(16)30003-9
DOI:
10.1016/j.preteyeres.2016.02.002
Reference:
JPRR 619
To appear in:
Progress in Retinal and Eye Research
Received Date: 11 December 2015 Revised Date:
7 February 2016
Accepted Date: 8 February 2016
Please cite this article as: Du, L., Kijlstra, A., Yang, P., Vogt-Koyanagi-Harada disease: Novel insights into pathophysiology, diagnosis and treatment, Progress in Retinal and Eye Research (2016), doi: 10.1016/j.preteyeres.2016.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment Liping Du1, Aize Kijlstra2,3, Peizeng Yang1
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1 The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China 2 University Eye Clinic Maastricht, Maastricht, Limburg, The Netherlands 3 Wageningen UR Livestock Research, Wageningen, The Netherlands * Correspondence to: Peizeng Yang, MD, PhD. Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, Chongqing, China. Tel: 86-023-89012851 Fax: 86-023-89012851 Email: [email protected]
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Abstract
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Vogt-Koyanagi-Harada (VKH) disease is one of the major vision-threatening diseases in certain
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populations, such as Asians, native Americans, Hispanics and Middle Easterners. It is
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characterized by bilateral uveitis that is frequently associated with neurological (meningeal),
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auditory, and integumentary manifestations. Although the etiology and pathogenesis of VKH
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disease need to be further elucidated, it is widely accepted that the clinical manifestations are
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caused by an autoimmune response directed against melanin associated antigens in the target
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organs, i.e. the eye, inner ear, meninges and skin. In the past decades, accumulating evidence has
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shown that genetic factors, including VKH disease specific risk factors (HLA-DR4) and general risk
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factors for immune mediated diseases (IL-23R), dysfunction of immune responses, including the
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innate and adaptive immune system and environmental triggering factors are all involved in the
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development of VKH disease. Clinically, the criteria of diagnosis for VKH disease have been further improved by the employment of novel imaging techniques for the eye. For the treatment,
early and adequate corticosteroids are still the mainstream regime for the disease. However,
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immunosuppressive and biological agents have shown benefit for the treatment of VKH disease,
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especially for those patients not responding to corticosteroids.
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This review is focused on our current knowledge of VKH disease, especially for the diagnosis,
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pathogenesis (genetic factors and immune mechanisms), ancillary tests and treatment. A better 1
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understanding of the role of microbiome composition, genetic basis and ongoing immune
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processes along with the development of novel biomarkers and objective quantitative assays to
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monitor intraocular inflammation are needed to improve current management of VKH patients.
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Keywords: Vogt-Koyanagi-Harada disease; Genetic background; immune mechanisms; clinical
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features; therapy
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Contents
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Abstract ..................................................................................................................................... 1
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Introduction ............................................................................................................................... 3
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History ....................................................................................................................................... 4
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Diagnostic criteria ...................................................................................................................... 5
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Epidemiology ............................................................................................................................. 8
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Etiology and pathogenesis....................................................................................................... 11
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Genetics ............................................................................................................................... 12
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HLA-antigens.................................................................................................................... 12
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Killer immunoglobulin-like receptors .............................................................................. 14
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Immunogenetics and VKH disease .................................................................................. 16
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Pathology ............................................................................................................................. 19
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Immunopathology ............................................................................................................... 20
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Antigens ........................................................................................................................... 21
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Immune responses .......................................................................................................... 22
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Triggering factors ............................................................................................................. 27
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Clinical features ....................................................................................................................... 28 Stage of VKH disease ........................................................................................................... 29 Prodromal stage .............................................................................................................. 29 Acute stage ...................................................................................................................... 29
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Chronic (convalescent) stage........................................................................................... 30
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Chronic recurrent stage ................................................................................................... 31
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Staging system in the Chinese population ...................................................................... 32
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Complications ...................................................................................................................... 32 2
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Ancillary tests ...................................................................................................................... 34
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Fluorescein angiography (FA) .......................................................................................... 34
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Ultrasonography .............................................................................................................. 34
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Lumbar puncture ............................................................................................................. 34
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Indocyanine green angiography (ICGA) ........................................................................... 35
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Optical coherence tomography (OCT) ............................................................................. 35
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Other ancillary tests ........................................................................................................ 36
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Therapy .................................................................................................................................... 37
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Corticosteroids .................................................................................................................... 37
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Immunosuppressive agents................................................................................................. 39
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Biologic agents..................................................................................................................... 40
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Management of VKH in special groups ............................................................................... 42
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Management of complications............................................................................................ 42
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Prognosis ................................................................................................................................. 43
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Future directions ..................................................................................................................... 45
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Acknowledgments ................................................................................................................... 46
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Competing financial interests.................................................................................................. 46
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Figure legends ......................................................................................................................... 46
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References ............................................................................................................................... 47
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Introduction
Vogt-Koyanagi-Harada (VKH) disease is an immune-mediated disorder characterized by
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bilateral uveitis frequently associated with neurological (meningeal), auditory, and integumentary manifestations.
The uveitis characteristic of VKH disease is generally divided into four stages or an
evolutionary four-step process: prodromal stage, acute uveitis stage, chronic convalescent stage
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and chronic recurrent stage (Moorthy et al., 1995; Read et al., 2001a). Neurological
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manifestations (including headache, neck and back stiffness, abnormal sensitivity to touch of the
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hair) and auditory manifestations (tinnitus, hearing loss and vertigo) usually occur before or
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concurrently with ocular involvement, whereas integumentary manifestations (including alopecia, 3
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poliosis and vitiligo) always arise after the uveitis attack (Fang and Yang, 2008; Moorthy et al.,
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1995; Read et al., 2001a).
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Although the etiology and pathogenesis of VKH disease is not completely known, a great number of studies in the past decades have shed more light on this issue. In individuals with a
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predisposing genetic background (HLA-DR4), certain environmental factors (for instance viral
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infection) trigger the immune response, especially the adaptive immune response. This leads to a
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Th1 and Th17 cell activation directed against self-antigens (for instance tyrosinase) expressed by
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melanocytes in various organs resulting in a multisystemic acute autoimmune disease.
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Although glucocorticosteroids and immunosuppressive agents are still the most often prescribed drugs for VKH disease, biologic anti-inflammatory (anti-TNF-α antibody) and
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anti-neovascular (anti-VEGF) therapy that have been introduced in the past two decades, offer
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promising modalities to patients with sight-threatening recurrent inflammation or severe
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neovascularization (Busanyova et al., 2013; Wu et al., 2009).
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With the rapid progress in immunology, genetics and technology, great progress has been made in both basic and clinical research of VKH disease. The present article aims to review the
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latest studies on the immune and genetic pathogenesis of VKH, the new techniques for diagnosis
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and follow-up, the latest treatment regime, as well as the definition, epidemiology, clinical
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features, and the gradual progress in criteria for diagnosis of VKH disease.
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History
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Vogt-Koyanagi-Harada disease was first described in a report on the association of
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nontraumatic idiopathic uveitis with poliosis by Vogt (Vogt, 1906). In this report, Vogt considered
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this condition as a new entity of unknown disease. Cases reported subsequently and the
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landmark reviews by Koyanagi (Koyanagi, 1929) in 1929 drew more attention of ophthalmologists
to the disease. A syndrome, bilateral non-traumatic uveitis with poliosis, vitiligo, alopecia and
dysacousia, was integrated from sixteen cases (10 from literature and 6 from his observation)
described in Koyanagi’s review (Koyanagi, 1929). Based on this extensive review and the
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uniformity among these cases, most authors agree that cases reported by Vogt and Koyanagi
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were indeed one disease entity and accepted the name Vogt-Koyanagi syndrome for this
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condition. On the other hand, the road for integration of Harada’s disease into Vogt-Koyanagi
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syndrome was not so smooth, even though Harada’s disease and Vogt-Koyanagi syndrome were 4
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considered as one condition early in 1932 by Babel (Babel, 1932). Harada’s disease was first
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described as a separate uveitis entity in 1926 (Harada, 1926)and was characterized by a
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complicated retinal detachment and pleocytosis in the cerebrospinal fluid (CSF). Subsequently,
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based on reports by Parker (Parker, 1940), Rados (Rados, 1940, 1941) and some others in the
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Japanese literature, earlier researchers were inclined to differentiate the Vogt-Koyanagi
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syndrome from Harada’s disease by the high rate of retinal detachment and alopecia with poliosis
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and lower rate of anterior uveal involvement in the latter. With the increasing numbers of reports
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for the intermediate form of bilateral uveitis with mixing features for two conditions, more and
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more researchers considered the two separate conditions as different clinical variations in a same
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underlying process (Bruno and McPherson, 1949; Cowper, 1951a). Recently, based on a study of
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410 Chinese VKH patients, we came to the conclusion that both conditions represent the clinical
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manifestations of an evolutionary disease process instead of being two separate disease entities
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(Yang et al., 2007). At the onset, the disease always shows a diffuse choroiditis frequently in
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association with exudative retinal detachment. The disease eventually progresses to a recurrent
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granulomatous anterior uveitis if no appropriate treatment is given.
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Various names have been given to this condition including “uveoencephalitis”,
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“Uveomeningoencephalitic Syndrome”, “Uveomeningoencephalitides” or
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“Uveomeningoencephalitis” (Cowper, 1951b; Vancea and Lazarescu, 1958). However,
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Vogt-Koyanagi-Harada disease/syndrome is now the most widely accepted term.
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Diagnostic criteria
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Several sets of criteria have been proposed for the diagnosis of VKH disease, since it was
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initially considered as a single clinical uveitis entity. The evolution of the criteria represents the
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process of our gradual understanding of the disease. Based on the observation of a bilateral
acute diffuse uveitis together with various typical extraocular features, the diagnosis of VKH
disease is not difficult, although there may be a great similarity between this disease and
sympathetic ophthalmia, which is also characterized by an acute bilateral uveitis with alopecia,
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vitiligo, poliosis and deafness. The latter however usually takes place after ocular trauma or
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intraocular surgery and rarely presents with extraocular manifestations. A consensus for
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diagnostic criteria of VKH disease was reached at the second annual meeting of the American
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Uveitis Society (AUS), in Kansas City, Missouri in 1978 (Snyder and Tessler, 1980) (Table 1). 5
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The AUS criteria were widely used in a series of studies since their appearance. Although the acceptance of AUS criteria facilitated the communication between different investigators,
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these criteria do not embody the different manifestations observed during disease progression.
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Two of the four criteria, namely b) and d), are features that are only observed in the late course
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of the disease. Using these criteria, it is therefore not easy to make a correct diagnosis of an early
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stage of VKH disease. These criteria were therefore not suitable for planning prospective studies
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of VKH disease (Read et al., 2001a). In addition, the AUS criteria did not include the evaluation by
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ultrasonography and fluorescein angiography, which has been shown to be of great help in the
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diagnosis of VKH disease (Forster et al., 1990).
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About the same time that the AUS criteria were published, a set of criteria were also
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proposed by Sugiura (Sugiura, 1976a, 1978). These latter criteria paid more attention to the
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manifestations observed during the early stages of disease. These features include acute bilateral
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uveitis, circumscribed retinal edema, pleocytosis of the CSF, depigmentation of the corneal
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limbus, dysacousia, vertigo and supersensitivity of the skin on touching the hair. Sugiura’s criteria
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thus seemed more suitable for the diagnosis of early VKH disease. However, Sugiura’s criteria
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were seldom accepted outside Japan for two reasons: depigmentation of the corneal limbus
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(Sugiura’s sign) is not often observed in patients with VKH disease outside Japan and due to the
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fact that these criteria include CSF analysis, which is an invasive test that is not performed in a
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department of Ophthalmology.
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the accuracy/sensitivity of the AUS criteria for the diagnosis of VKH disease. In that study, 71
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consecutive patients with VKH disease were evaluated according to the AUS diagnostic criteria
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with manifestations present at the initial presentation. The results showed that patients presenting in the acute, subacute and chronic stages met the AUS criteria for VKH disease in 56%,
48% and 58% of cases, respectively (Read and Rao, 2000). This study showed that the AUS criteria
were not adequate for the evaluation of patients with VKH disease. Therefore, more precise
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diagnostic criteria with increased sensitivity and specificity were needed for both the clinical
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ophthalmologist and basic science investigators. Revised Diagnostic Criteria (RDC) for VKH
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disease were proposed at the First International Workshop on Vogt-Koyanagi-Harada Disease on
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October 19-21, 1999 in California (Read et al., 2001a) (Table 3). 6
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The revised criteria have the advantage that they include the difference in clinical manifestations of VKH disease at varying stages of the disease and that it uses the results of
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ancillary examinations (fluorescein angiography and ultrasonography). The ocular manifestations
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are more comprehensively delineated according to the early and late stages of the disease. The
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RDC includes five sections: the exclusion criteria for sympathetic ophthalmia, the exclusion of
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other uveitis entities (sarcoidosis, syphilitic uveitis, tuberculous uveitis, Lyme disease, posterior
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scleritis, intraocular lymphoma, central serous choroidopathy, uveal effusion syndrome), the
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ocular manifestations of the early and late stages, the neurological/auditory findings and the
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integumentary findings. It divides VKH disease into three categories, “complete”, “incomplete”
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and “probable” (Table 3). For the complete type, bilateral ocular involvement,
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neurological/auditory findings and integumentary abnormalities must be present, while the
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incomplete type has either neurological/auditory or integumentary symptoms. The probable type
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has only ocular manifestations. The first two categories are considered as a certain diagnosis. The
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probable VKH disease category, also referred to as “ocular VKH disease”, needs a continued
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surveillance for signs that would confirm or refute the definite diagnosis of VKH disease (Read et
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al., 2001a).
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Since the appearance of the RDC in 2001, various comparisons with the Sugiura criteria were published (Cardoso et al., 2008; da Silva et al., 2009a; Kitamura et al., 2005; Rao et al., 2007;
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Yamaki et al., 2005) in different ethnic groups. Yamaki et al. (Yamaki et al., 2005) studied 49
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patients with VKH disease diagnosed at the Akita University School of Medicine Hospital and
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re-classified them into complete and incomplete VKH disease according to the RDC. In their
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assessment the RDC was not as effective as Sugiura’s criteria for establishing the diagnosis at the
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early stages of VKH disease (Yamaki et al., 2005). This is not surprising since 40.9% of their VKH patients only had ocular manifestations (Rao et al., 2007). If the probable VKH disease was
considered as a category of VKH disease in that study, the RDC would have been as sensitive as Sugiura’s criteria. The RDC were also compared to the Sugiura’s criteria by Kitamura et al.
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(Kitamura et al., 2005) and to the AUS criteria by da Silva et al. (da Silva et al., 2009a) and to both
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criteria by Rao et al. (Rao et al., 2007). These studies all showed that the RDC is highly sensitive
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and specific for the diagnosis of VKH disease both at the early and late stages. Our own studies
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showed that the RDC is very useful for the diagnosis of Chinese VKH patients (Yang et al., 2007). 7
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In our uveitis clinic, we observed that some patients presenting with a sunset glow fundus and
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Dalen-Fuchs nodules had a typical evolutionary process of uveitis and lacked extraocular
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manifestations before the onset of uveitis and during the whole follow-up time. We classified
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these patients, which should be considered as probable VKH disease according to the RDC, as
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ocular VKH disease (Yang, 2004). A recent prospective international study performed by Rao et al.
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(Rao et al., 2010) showed that VKH disease can present in patients with clinical findings limited to
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the eye without extraocular findings in the form of bilateral uveitis associated with exudative
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retinal detachment at the early stage or in the form of sunset glow fundus at the late stage. This
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study reinforced the importance of the diagnosis of the probable VKH disease category in the
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RDC classification. Based on these features, we would like to argue that the probable VKH disease
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category should be considered as a genuine ocular VKH disease characterized by a lack of
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extraocular manifestations.
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Epidemiology
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Although population-based epidemiological studies about VKH disease are relatively rare, epidemiological data based on studies from tertiary referral centers have shown that the
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incidence of VKH disease varies greatly worldwide. VKH disease is one of the most common
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diseases causing panuveitis in North Asia, accounting for 7%-10% of all uveitis referrals (Kotake et
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al., 1997; Ohguro et al., 2012; Sugita et al., 1993; Wakabayashi et al., 2003) in Japan and
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11%-22.4% in Thailand (Pathanapitoon et al., 2008; Silpa-Archa et al., 2014). Results from 1752
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uveitis patients referred to our uveitis clinic showed that VKH disease was the second most
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common entity causing panuveitis, accounting for 15.9% of all uveitis cases in China (Yang et al.,
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2005). The incidence of VKH disease is also high in the Middle East. It was reported to be
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19.4%-19.6% of all uveitis cases in Saudi Arabia (Al-Mezaine et al., 2010; Al Dhahri et al., 2014)
and 12.3% in Iraq (Al-Shakarchi, 2014). This was much higher than the 3.9% of all 544 uveitis
cases reported in Iran by Soheilian et al (Soheilian et al., 2004). A study from Tunesia showed that
4.4% of 472 uveitis cases had VKH disease (Khairallah et al., 2007a). According to Couto and
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Merlo (Couto and Merlo, 1993), VKH disease is also common in South America and it was the
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most common cause of panuveitis accounting for 13.3% of all uveitis referrals in Argentina and
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17.2% in Chile (Liberman et al., 2014). VKH accounts for 1.2%-2.2% of uveitis case encountered in
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India (Martin et al., 2010; Mondkar et al., 2000). In contrast to the high prevalence of VKH 8
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disease in the populations described above, it is relatively less frequent in European populations
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such as England (＜1%) (Perkins and Folk, 1984), the Netherlands (＜1%) (Rothova et al., 1992;
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Smit et al., 1993), Finland (none mentioned) (Paivonsalo-Hietanen et al., 2000;
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Paivonsalo-Hietanen et al., 1994),Turkey (1%) (Sengun et al., 2005; Tugal-Tutkun et al., 2007),
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Austria (0.4%) (Barisani-Asenbauer et al., 2012), and Italy (1.4%-2.1%) (Cimino et al., 2010;
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Mercanti et al., 2001; Pivetti-Pezzi et al., 1996b). It accounts for 1%-4% of all uveitis referrals in
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the United States (Ohno et al., 1977; Snyder and Tessler, 1980). The relative higher incidence of
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VKH disease when compared with that in European populations may be due to the multiple
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ethnic populations residing in the USA (Beniz et al., 1991; Nussenblatt, 1988). Some investigators
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reported that 54%-78% of VKH patients in the US had a Hispanic background (Moorthy et al.,
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1995; Rubsamen and Gass, 1991), whereas others claimed that Asian and American Indians
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comprised the majority of VKH patients in this country (Nussenblatt, 1988; Ohno et al., 1977).
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The presence of many individuals with a Hispanic or Asian background may contribute to the
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incidence of VKH disease in the United States. Therefore, based on these epidemiological studies
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from tertiary referral centers, it is now widely accepted that VKH disease affects certain heavily
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pigmented populations (Asians, Hispanics, American Indians, and middle Easterners) and is rarely
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seen in Caucasians in Europe and Black people in Africa (Rao et al., 1995; Read et al., 2001a;
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Sugiura, 1978). If pigmentation would be the major risk factor for VKH disease, then one would
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expect a high incidence in the Black population in Africa. They are rarely affected by VKH disease,
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which indicates that there might be differences in the pigmentation pathways in blacks as
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compared to other heavy pigmented populations in the world. If ethnicity would be a critical risk
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factor for VKH disease, one would expect that populations from the same ethnic background
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would have a similar incidence. As a matter of fact, the incidence of VKH disease varies greatly in
subpopulations of the same ethnicity. There is for instance a great difference in the incidence of
VKH disease between an Arab population from Saudi Arabia (Al-Mezaine et al., 2010) as
compared to an Arab population from Iran or Tunisia (Khairallah et al., 2007a; Soheilian et al.,
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2004). This would argue in favor of a role for an environmental factor between these countries
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since the genetic background of the population is expected to be very similar. The very low
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prevalence of disease in a neighboring country such as Turkey is also unexpected although the
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ethnic majority of this population does not consist of Arabs but is made up of Turks (Sengun et al., 9
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2005; Tugal-Tutkun et al., 2007). Also, the incidence (2%) of VKH disease reported in Korea
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(Chung and Choi, 1989) was much lower than that in other East Asian populations, such as in
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Japan, China and Thailand (Kotake et al., 1997; Sugita et al., 1993; Wakabayashi et al., 2003; Yang
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et al., 2007). In addition, a Hispanic background was reported to represent the majority of
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patients with VKH disease in the United States (Moorthy et al., 1995; Rubsamen and Gass, 1991).
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However, in an urban multi-ethnic population from Barcelona (Spain), 19 patients with VKH
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disease only accounted for about 1% of all 1022 patients with uveitis (Llorenc et al., 2015). Of
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these 19 patients, 9 patients were born in South America (Llorenc et al., 2015). Genetic
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susceptibility plays an important role in the development of VKH disease and it is possible that
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with the global migration of ethnic populations, selection has taken place thereby changing the
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genetic predisposition to VKH. On the other hand environmental factors such as certain microbial
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infections may also play a role and the exposure of similar ethnic populations to other
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environmental circumstances may explain differences in the prevalence of an autoimmune
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disease such as VKH.
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VKH disease predominantly affects people in their second to fifth decade of life (Moorthy et al., 1995; Yang et al., 2007), though children as young as 3 years (Al Hemidan et al., 2006;
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Takada et al., 2015) and elderly patients as old as 89 years have also been reported (Yamamoto et
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al., 2007). Although a number of pediatric patients with VKH disease were reported, including
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several studies from tertiary centers (Table 4), VKH disease in children is relatively uncommon
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(Martin et al., 2010). Pediatric patients (age ≤16 years) with VKH disease accounted for 3.1% to
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13.4% of all patients with VKH disease (Table 4) (Martin et al., 2010; Rathinam et al., 1998;
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Tabbara et al., 1998). In addition, based on information of 128 pediatric patients with VKH
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disease, girls were more likely to be affected (Martin et al., 2010). As for elderly patients with
VKH disease, one study suggested that the ratio of elderly VKH patients has increased yearly. Of the 68 patients with VKH disease reported by Kiyomoto et al (Kiyomoto et al., 2007), seven (10%)
were classified as elderly (age ≥65 years) at onset.
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Gender plays a role in the occurrence of VKH disease (Wang and Chan, 2014). Most studies
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revealed that 55%-78.3% of VKH patients were female (Table 5). In our own studies in 410
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Chinese patients we did not find a gender effect (Yang et al., 2007). In Japan, a varying gender
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ratio has been reported by different investigators. Although Sugiura (Sugiura, 1978) did not 10
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observe a gender effect, other investigators found that males were less likely to be affected than
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females (Horie et al., 2009; Yamaki et al., 2005). On the other hand, Sasamoto et al. (Sasamoto et
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al., 1990) reported that 29 (61.7%) of their 47 patients with VKH disease were male. A recent
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prospective study performed by 10 uveitis centers showed that 75% of patients with acute uveitis
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caused by VKH disease were female, while the female frequency was 68.1% in patients with
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chronic uveitis caused by this disease (Rao et al., 2010). It thus appears that females are more
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likely to develop VKH disease, although the differences in sexual dimorphism are small (table 5).
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A possible explanation for gender differences found in VKH include a role for sex hormones,
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including estrogen and progesterone, that are believed to account for gender differences in the
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prevalence of autoimmune disorders in general (Wang and Chan, 2014).
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Etiology and pathogenesis
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Although the precise etiology and pathogenesis of VKH disease remains to be elucidated,
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great progress has been made during past decades with the rapid development in various fields
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of basic science. Viruses discovered in patients with VKH disease reinforce the triggering role of a
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microbial infection in the disease. Meningeal manifestations, such as fever, headache and
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meningismus in the prodromal stage have led to the hypothesis that a viral infection might
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provoke VKH disease. The group of Mochizuki has provided evidence for a role of
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cytomegalovirus in this disease (Sugita et al., 2007; Sugita et al., 2006), although earlier studies
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suggested herpes viruses were not involved (Hotta et al., 1996). The strong association with
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HLA-class II alleles and Th1 and Th17 cells would not be in favor of a viral pathogenesis since then
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one would expect a link with HLA-class I and CD8 cells. On the other hand, a viral infection may
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indirectly cause VKH disease as a triggering factor, whereby a disease association with HLA-class I
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alleles is not necessary. In this hypothesis, certain viral antigens may mimic self-proteins which
can be recognized by specific HLA-class II molecules (molecular mimicry), subsequently triggering
the inflammatory autoimmune response. Further research is needed to substantiate the viral hypothesis to be sure that it is not a spurious link. Monozygotic twins affected by VKH disease and the strong association with the human
333
leukocyte antigens DR4 and DRw53 (HLA-DR4 and HLA-DRw53) indicates that it may occur in
334
individuals with a susceptible genetic background. The discovery of uveal antigens, such as
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S-antigen, interphotoreceptor retinoid binding protein (IRBP) (Chan et al., 1985) and tyrosinase 11
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(or tyrosinase-related proteins) (Sugita et al., 1996) lays a foundation for the autoimmune nature
337
of this disease. Immune cells located within choroidal inflammatory foci, T helper (Th) cells
338
(including Th1 and Th17) and cytokines involved in this diseases emphasize the critical role of the
339
immune response in its pathogenesis (Andreoli and Foster, 2006; Chi et al., 2007; Imai et al., 2001;
340
Li et al., 2005; Miyazawa et al., 2005; Norose and Yano, 1996). Currently, evidence accumulated in
341
the past decades suggests that VKH disease occurs in individuals with a predisposing genetic
342
background. The disease is triggered by as yet unknown factors leading to an immune response
343
directed against certain autoantigens (Fig 1). We will provide further details concerning this
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statement in the following sections.
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Genetics
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HLA-antigens
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First of all, VKH disease is not a genetic disease complying with Mendelian inheritance and it usually occurs sporadically. The genetic role in the pathogenesis of the disease is intuitively
349
recognized by the high incidence of the disease in populations with heavier pigmentation and the
350
coincidence in siblings (Benedict and Benedict, 1951) or monozygotic twins (Ashkenazi et al.,
351
1991; Ishikawa et al., 1994; Itho et al., 1992). A genetic predisposition became apparent when a
352
strong association was found with certain HLA antigens (Supplementary Table 1). The HLA
353
antigens first reported to be associated with VKH disease in Japan were HLA-BW22J and LD-Wa
354
(Tagawa et al., 1976; Yakura et al., 1976), although Ohno et al (Ohno et al., 1976) were not able to
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replicate the association in 9 VKH patients in California. The discrepancy between these two
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studies might be due to a different genetic background in different ethnic populations or the
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small sample size. These first studies were soon overshadowed by the strong association in
Japanese patients with two other HLA antigens, namely HLA-DR4 and HLA-DRw53 (Ohno, 1981).
The confirmation of this association in other ethnic populations was first reported in Chinese Han.
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Twenty-five Chinese Han patients with VKH disease and 65 healthy controls were genotyped for
361
HLA-A, B and DR alleles by Zhao et al (Zhao et al., 1991) and results showed that HLA-DRw53
362
(positive in all 25 patients) and HLA-DR4 (positive in 20 patients) was indeed closely associated
363
with VKH disease with a relative risk of 16.0 and 34.2, respectively (Zhao et al., 1991). 12
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Subsequently, this association was replicated in different ethnic populations, such as American
365
(Davis et al., 1990), Hispanic (Weisz et al., 1995), Vietnamese (Riddington et al., 1996), Italian
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(Pivetti-Pezzi et al., 1996a), Brazilian (Goldberg et al., 1998), Mexican (Arellanes-Garcia et al.,
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1998) and Korean (Kim et al., 2000) patients, though some novel VKH disease associated HLA
368
antigens, such as HLA-DQw3, were also identified in certain populations. Furthermore, other
369
HLA-antigens, such as HLA-B54, HLA-DQ4 and HLA-DR1 (sharing a common epitope with HLA-DR4
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encoded by the HLA-DRβ-1 gene), were also shown to be associated with VKH disease, although
371
the associations appeared to be population dependent (Islam et al., 1994; Shindo et al., 1994;
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Weisz et al., 1995). With the development of newer methods for HLA genotyping, HLA antigens in
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patients with VKH disease were subsequently mapped at the genomic level. In two independent
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original studies, HLA-DRB1*0405, HLA-DQA1*0301 and HLA-DQB1*0401 alleles have been shown
375
to predominate in Japan (Islam et al., 1994; Shindo et al., 1994), although Islam et al (Islam et al.,
376
1994) identified DQA1*0301, while Shindo et al (Shindo et al., 1994) concluded that two other
377
alleles (HLA-DRB1*0405 and HLA-DQB1*0401) were the primary susceptibility factor for VKH
378
disease. The strong association of HLA-DRB1*0405 and HLA-DQB1*0401 with VKH disease was
379
confirmed in China (Min et al., 2007; Xiao et al., 1997; Zhang et al., 2000), Brazil (Goldberg et al.,
380
1998), Korea (Kim et al., 2000) and Saudi Arabia (Iqniebi et al., 2009). It could not be confirmed
381
for Hispanics in Southern California and Mexican mestizo (Alaez et al., 1999; Arellanes-Garcia et
382
al., 1998; Levinson et al., 2004; Weisz et al., 1995). Hispanic and mestizo patients in fact showed a
383
weak association with HLA-DR1 and DR4. As for the HLA alleles, these patients showed an
384
association with HLA-DRB1*0404/*0407/*0410 and HLA-DQA1*03011/80302 (Arellanes-Garcia
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et al., 1998; Levinson et al., 2004). Alaez et al. (Alaez et al., 2011) found that HLA-DRB1∗04:05,
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HLA-DRB1∗04:04, and HLA-DQB1∗03:02 HLA alleles were restricted only to female VKH patients,
implying an association of HLA antigens with female predilection in VKH. Recently, we performed
a genome-wide association study to explore the genetic background for VKH disease. Our study
confirmed the strong association of the HLA gene region with VKH disease and several VKH
390
disease associated SNPs were identified (Hou et al., 2014a). However, because of the complexity
391
of these region, the relation of these VKH associated SNPs should further be assessed by fine
392
DNA sequencing. Which of the VKH-disease-associated HLA class II antigens, is most important in
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conferring susceptibilitiy to VKH disease remains to be solved. It appears that multiple 13
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HLA-antigens or alleles can confer risk for VKH disease depending on the ethnic population. A
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systematic review and meta-analysis for 1853 VKH patients and 4164 controls from 21 articles
396
showed that the strength of association depends on the ethnic group investigated (Shi et al.,
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2014). HLA-DRB1*0404, 0405 and 0410 are risk sub-alleles for VKH disease, while 0401 is a
398
protective sub-allele (Shi et al., 2014).
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HLA-DRB1 is expressed on the cell surface and acts as a receptor, that binds a specific
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peptide, and depending on the genetically determined configuration of its antigen binding groove,
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can present this to cells of the immune system. If cells of the immune system contain a matching
402
receptor for the HLA-DRB1-peptide complex it will result in an expansion of these cells finally
403
leading to an attack of tissues expressing these peptides. As mentioned earlier, VKH patients are
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sensitized to melanocyte antigens and an explanation concerning a possible association of certain
405
genetic HLA-DRB1 variants with the disease is sought in differences in their melanocyte peptide
406
binding capacity. In this context it has been proposed that the risk HLA-DRB1*0405 may
407
recognize a broad melanocyte-antigen peptide repertoire, whereas the protective
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HLA-DRB1*0401 may have a limited binding capacity for melanocyte associated antigens (Damico
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et al., 2005a; Shi et al., 2014).
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Of interest is the observation that an association has only been observed with HLA class II antigens and not with class I antigens. HLA class II is thought to be involved in the presentation of
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extracellular antigens to T cells, whereas HLA class I molecules present intracellular antigens.
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Different HLA antigens or alleles, which may precipitate the onset of the disease or determine the
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clinical course of the disease in different populations, could present the same immunogenic
415
peptides to immune cells. Although a number of studies predicting HLA binding of antigens in
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silico and studies examing common peptides for different HLA-antigens were performed
(Hennecke and Wiley, 2002; Prasad and Levinson, 2005; Shindo et al., 1994; Sugita et al., 2006),
further studies are needed to provide additional insight into the possible mechanisms explaining the association between certain HLA antigens and VKH disease. Killer immunoglobulin-like receptors Killer immunoglobulin-like receptors (KIR), clustering on Chromosome 19q13.4, can either activate or inhibit natural killer cells and certain subsets of T lymphocytes (Lanier, 2005; Vilches 14
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and Parham, 2002). KIRs are generally divided into inhibitory KIRs (2DL1, 2, 3, 5 and 3DL1, 2, 3)
424
and activating KIRs (2DS1, 2, 3, 4, 5 and 3DS1). HLA class I genes serve as the ligands for certain
425
KIRs (such as 2DL1 and HLA-C2, 2DL2/2DL3 and HLA-C1, 3DL1 and HLA-Bw4). Specific KIR-HLA
426
combinations present in certain individuals may play a critical role in determining the individuals’
427
immune status and predilection to disease (Single et al., 2008). Also, numbers of KIR genes and
428
patterns of these genes make them a useful tool, just like HLA antigens, for analysing the genetic
429
background of susceptibility to human inflammatory, neoplastic, infectious disease and
430
autoimmune disease (Kulkarni et al., 2008), including VKH disease (Levinson et al., 2008; Levinson
431
et al., 2010; Sheereen et al., 2011). Though there was no evidence for a strong association of HLA
432
class I genes with VKH disease, KIRs and related HLA genes were assayed in 24 Mestizo patients
433
with VKH disease from Southern California by Levinson et al (Levinson et al., 2008). No specific
434
genes were identified to be associated with VKH disease, but a trend of more haplogroups with
435
activating KIRs in patients (p=0.59) was observed (Levinson et al., 2008). In addition, some
436
inhibitory KIR-HLA combinations were more common in controls than in patients, though the
437
differences were not statistically significant. To eliminate the influence of genetic diversity on
438
data analysis within this study, Levinson et al (Levinson et al., 2010) conducted another study
439
examing whether the KIR genes could influence susceptibility to VKH disease in Japanese (26
440
patients and 173 controls). This sample was considered as a highly homogeneous population. The
441
result showed a decreased freqency of 3DL1 (inhibitory KIR) (p=0.00006, OR=0.039) and an
442
increased frequency of activating B haplogroups (p=0.01,OR=3.1) in patients when compared to
443
controls. Activating KIR genes 3DS1, 2DS1 and 2DS5 were more frequently seen in patients
444
compared with controls (42.2% vs 21.4%, p=0.02). Most recently, KIRs and HLA-C alleles were
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typed for 30 patients with VKH disease and 125 controls from Saudi Arabia by Sheereen et al
(Sheereen et al., 2011). Results showed a significantly higher frequency of KIR2DS3, HLA-Cw*14,
HLA-Cw*17 and genotype Bx5 (one haplotype carrying two aKIRs, 2DS2 and 2DS4) in patients compared to controls. Among potential KIR-HLA interactions, the combination of inhibitory
449
KIR2DL2/2DL3 and HLA-C1 was less frequently observed in VKH patients (p=0.018). Therefore,
450
certain KIRs may confer susceptibility to VKH disease in different populations, though
451
disease-related KIRs, just like disease-related HLA antigens, were different depending on the
452
originating population. For a better understanding of the association of KIRs and VKH disease, 15
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more studies are needed to investigate the mechanisms how KIRs’ are involved in the regulation
454
of cells expressing these molecules (Natural Killer cells and some T lymphocytes ) and the
455
involvement of these cells in VKH disease.
456
Immunogenetics and VKH disease
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The association between the HLA system and KIRs with VKH disease does not fully explain the genetic risk for VKH syndrome. These genes play an important role in the antigen
459
presentation phase of the immune response, but other downstream pathways which have been
460
shown to be polymorphic may also play a role in the genetic predisposition to VKH. Recently,
461
studies on the association of certain important functional genes (Fig 2) involved in the immune
462
response with this disease have further highlighted the genetic background of VKH disease
463
(Supplementary Table 2). Horie et al (Horie et al., 2006) were the first to hypothesize that
464
polymorphisms in the tyrosinase gene family loci could act as predisposing genes for VKH disease,
465
because tyrosinase-related proteins have been shown to be one of the autoantigens involved in
466
VKH disease (Yamaki et al., 2000a). They examined 7 microsatellite polymorphisms around the
467
loci for 87 patients with VKH disease and 122 healthy controls from Japan but found no
468
association between these polymorphisms and VKH disease. These results do not contradict the
469
critical role of tyrosinase-related proteins in VKH disease (Yamaki et al., 2000a), because a genetic
470
polymorphism in the autoantigen may not necessarily alter the immunogenic epitopes that
471
drives the autoimmune response directed to it. Polymorphisms of other genes controlling an
472
autoimmune response may on the other hand be involved in the susceptibility to VKH disease.
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We therefore started a series of studies addressing the role of polymorphisms of various
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immunological pathways in the pathogenesis of VKH disease. One of our first studies included the
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analysis of four genetic polymorphisms of the cytotoxic T lymphocyte-associated antigen-4
(CTLA-4) gene, which encodes a critical negative regulator of the T cell-mediated immune response. We performed this study in 209 patients with VKH disease and 256 controls of Chinese
478
ethnicity (Du et al., 2008). The results showed significantly higher frequencies of the G allele at
479
the + 49 site (71.6% versus 62.8%, P = 0.0046, Pc = 0.037) and the haplotype − 1661A:− 318C:+
480
49G: CT60G (70.1% versus 60.0%, P= 0.0013, n= 16, Pc= 0.021) in patients than in healthy
481
controls (Du et al., 2008). Following these studies, Ohno’s group and our group performed a 16
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series of studies to investigate the association of several candidate genes with VKH disease in
483
Japanese and Chinese patients, including IFN-γ (Horie et al., 2007), SUMO4 (Hou et al., 2008),
484
PTPN22 (Horie et al., 2009; Zhang et al., 2014), FCRL3 (Li et al., 2009), PDCD1 (Meng et al., 2009),
485
STAT4 (Hu et al., 2010), IL-23R (Jiang et al., 2010b), IL-17 (Shu et al., 2010), OPN (Chu et al., 2011),
486
TLR9 (Ito et al., 2011), NLRP1 (Horie et al., 2011), CD40 (Chen et al., 2012a), TGFBR3 (Chen et al.,
487
2012b), miR-146a (Zhou et al., 2012), Ets-1 (Zhou et al., 2012), TNFAIP3 (Li et al., 2013b), JAK1
488
(Hu et al., 2013), FGFR10P (Yi et al., 2013), IL-12B, IL-12Rβ1/β2 (Li et al., 2014), DHCR7, CYP2R1,
489
CYP27B1, and CYP24A1 (Fang et al., 2014), TNIP1 (Kanda et al., 2014), TRAF5 and TRAF3IP2
490
(Xiang et al., 2014), miR-182 (Yu et al., 2014), Bach2 (Gao et al., 2015) and CLEC16A (Li et al.,
491
2015) (Table 6). Studies on IFN-γ, PTPN22 and NLRP1 in Japanese and studies on SUMO4, IL-23R,
492
CD40, TGFBR3, miR-146a, Ets-1, Bach2 in Chinese failed to find an association with VKH disease.
493
Polymorphisms of FCRL3, JAK1, FGFR10P, PDCD1, STAT4, IL-17, IL-12B, OPN, TNIP1, TRAF5,
494
TRAF3IP2, miR-182, PTPN22 and CLEC16A, on the other hand have been shown to be associated
495
with VKH disease in Chinese patients. These studies partially confirm the hypothesis that
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polymorphisms of genes involved in the immune response confer susceptibility to VKH disease
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and broaden our understanding of the genetic background of this disease.
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In addition to microsatellites and SNPs, recently, copy number variations (CNVs), which are characterized by insertions, deletions, and duplications of genomic sequences ranging from a
500
kilobase to multiple megabase-long pairs, also have been demonstrated as one of the important
501
genetic markers for diseases with complex traits. We employed CNVs as a genetic marker to
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further assess the association of immune related genes with VKH disease (Supplementary Table
503
3). We firstly evaluated the association of complement 4 (C4) with VKH disease using CNVs as a
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genetic marker. Our results demonstrated that lower CNVs of the C4 gene confer risk for VKH syndrome, which may be caused by a decreased expression of the C4 gene in those patients (Hou
et al., 2014b). Subsequently, we assessed the relationship of complement components (C3, C4,
C5, C6, C7, C8A, C8B and C9) (Hou et al., 2014b), Toll-like receptors (TLR1-3, TLR5-7, TLR9 and
508
TLR10) (Fang et al., 2015), key transcription factors for differentiation of CD4+ T cell (TBX21,
509
GATA3, RoRγ and Foxp3) (Liao et al., 2015), genes involved in the IL-17/IL-23 pathway (IL17A,
510
IL17F, IL23A and IL23R) (Hou et al., 2015) and genes related to apoptosis (FAS, CASPASE8,
511
CASPASE3, and BCL2) (Yu et al., 2015). Higher copy numbers of C3, C4, IL-17F, IL-23A and FAS 17
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512
have been shown to be associated with VKH disease and the association may be partly explained
513
by the different gene expression profiles that are dependent on the gene copy number
514
(Supplementary Table 3). Interestingly, several genes predisposing to VKH disease, including IL-12B (Li et al., 2014);
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MIF (Zheng et al., 2012); TNFAIP3 (Li et al., 2013a); TRAF5 and TRAF3IP2 (Xiang et al., 2014);
517
IL17F and IL23A (Hou et al., 2015); C3 (Xu et al., 2015) and FAS (Yu et al., 2015), have also been
518
shown to be associated with Behcet’s disease, another common immune-mediated panuveitis in
519
China, though the specific disease-associated alleles in the same gene may be different for the
520
two diseases. These results indicated a common genetic basis between two immune-mediated
521
panuveitis entities. Genetic variations which mediate the immune response have been proposed
522
as common disease-associated genetic factors (Burton et al., 2007; Parkes et al., 2013;
523
Zhernakova et al., 2009). However, some diseases may be associated with unique disease-specific
524
genetic factors. Genome-wide association studies (GWAS) on VKH disease may provide more
525
insight into the role of genetic factors, both the common disease associated genetic factors and
526
VKH disease specific genetic factors in this disease. Our recent GWAS on VKH disease indeed
527
identified three loci associated with VKH disease susceptibility: IL23R-C1orf141,
528
ADO-ZNF365-EGR2 and HLA-DRB1/DQA1 (Hou et al., 2014a). The IL23R-C1orf141 and
529
HLA-DRB1/DQA1 loci were two of the common genetic factors that are also shared with other
530
immune-mediated diseases (Parkes et al., 2013; Zhernakova et al., 2009). The VKH disease
531
specific SNP rs442309 did not affect the expression of the genes ADO, ZNF365 and EGR2 in this
532
region (Hou et al., 2014a). Our GWAS study thus confirmed the role of HLA-DRB1/DQA1 as a
533
specific predisposing genetic factor to VKH disease while it failed to find new VKH disease specific
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predisposing genetic factors. More recently, we conducted a candidate genes association study
for VKH disease in multinational populations, including Chinese Singaporeans, non-Han Chinese,
Thailand and Koreans. Our results confirmed the genetic associations between SNPs in
IL23R-C1orf141 and VKH syndrome in Chinese Singaporeans but not in other Asian populations (in press). Based on the analysis above, limitations in immunogenetic studies are obvious. Firstly, the
540
associations identified using SNPs or CNVs were moderate and to date most of them were
541
reported for VKH patients from China. Replication of these associations in different populations is 18
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required. Secondly, because of the linkage equilibrium, most of the VKH disease associated
543
genetic markers, including SNPs, are probably not the true causative factors for the disease.
544
Novel methods to identify the real causative genetic factors for VKH associated genetic markers
545
are necessary to make further progress in the field. Thirdly, one should keep in mind that genes
546
interact with each other and to date most studies only focus on the role of single genes and do
547
not yet account for gene networks in the predisposition to disease.
548
Pathology
Historically, VKH disease is primarily considered as a non-necrotizing diffuse
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granulomatous inflammation of the uveal tract similar to sympathetic ophthalmia. Pathological
551
features were characterized by the presence of nodular lesions consisting of epithelioid cells
552
surrounded by a wall of lymphocytes and plasma cells (Ikui and Mimura, 1970; Ikui et al., 1959).
553
The origin of the epithelioid cells, which have been extensively studied in eyes with sympathetic
554
ophthalmia, were believed to be altered melanocytes (Ikui and Mimura, 1970; Miura and Ikui,
555
1970) or derived from monocytes and histiocytes (Matsuda, 1970). However, an
556
immunohistochemical study performed by Rao et al (Rao et al., 1985) demonstrated that these
557
epithelioid cells showed a positive staining with muramidase, S-100 protein and binding of
558
peanut lectin suggesting that the cells could be identified as tissue macrophages.
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According to early studies, the choriocapillaris, the retinal pigment epithelium and retina are usually spared during the early stage of VKH disease partly due to the possible role of RPE
561
cells in suppressing inflammation (Rao, 1997). However, with the progress of the disease,
562
granulomatous choroiditis with damage of the choriocapillaris, depigmentation, pigment
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dispersion and pigment phagocytosis is prominent at the chronic recurrent stage of the disease. Recently, Spectral-Domain Optical coherence tomography (SDOCT) provided non-invasive high
speed, high resolution, three-dimensional cross-section imaging of the RPE changes
(Vasconcelos-Santos et al., 2010). Observations by SDOCT have demonstrated that even at the
567
early stage, RPE cells are severely affected, presenting as folds of RPE (Lin et al., 2014; Tsuboi et
568
al., 2015). At the convalescent stage of VKH, the choroid is significantly thinner and the
569
choriocapillaris layer is disrupted (Nazari et al., 2014). Evaluation of the choriocapillaris in SD-OCT
570
scans may be a useful tool for evaluating the degree of disease severity and may also be helpful 19
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in predicting the prognosis of VKH disease. Another typical histologic feature in VKH disease are the Dalen-Fuchs nodules. They
573
usually manifest as a hemispherical mound between the RPE and Bruch’s membrane consisting of
574
lymphocytes, macrophages, epithelioid cells, and proliferated RPE cells (Reynard et al., 1985).
575
Clinically, the depigmented, small, round to oval lesions appearing at the chronic stage of disease
576
were considered to represent Dalen-Fuchs nodules. However, a histopathologic study by Inomata
577
et al (Inomata and Rao, 2001) have shown that these clinically visible lesions represent locally
578
damaged or disappeared retinal pigment epithelial cells, not corresponding to the
579
histopathological Dalen-Fuchs nodules. In addition, Inomata et al (Inomata and Rao, 2001) have
580
shown that Dalen-Fuchs nodules are made up of mainly lymphocytes and macrophages in the
581
early stage and a group of proliferated retinal pigment epithelial cells with few inflammatory cells
582
at the convalescent stage.
583
Immunopathology
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Immunohistochemical studies on eyes of patients with VKH disease lay the first stone for the basis of cells and molecules responsible for the immune response involved in the ocular
586
inflammation leading to VKH disease. Some of the early studies were hampered by the fact that
587
only morphological criteria were used to identify immune cells but were later expanded by using
588
monoclonal antibodies to determine the cellular subtypes (Sugiura and Matsuda, 1971). Inomata
589
et al (Inomata and Sakamoto, 1990) examined 4 eyes obtained from two patients with VKH
590
disease (one died 32 months after the onset of VKH and the other died 7 years after onset) and
591
observed a scattered infiltration of lymphocytes in a thickened choroid with a remarkable
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disappearance of choroidal melanocytes by immunohistochemistry. Furthermore, T and B lymphocytes were identified by immunohistochemical methods with monoclonal antibodies.
Approximately 70% of the lymphocytes were identified as T cells (Inomata and Sakamoto, 1990).
The results confirmed previous reports by Chan et al (Chan et al., 1988). Sakamoto et al
596
(Sakamoto et al., 1991) also confirmed that the choroidal infiltrate was composed predominantly
597
of T lymphocytes with a larger proportion of helper T cells than suppressor/cytotoxic T cells. In
598
addition, choroidal melanocytes and the endothelium of the choriocapillaris were found to
599
express HLA class II antigens. With the close contact between lymphocytes and melanocytes 20
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found previously (Sugiura, 1976b; Sugiura and Matsuda, 1971), these results indicated that
601
cell-mediated immune mechanisms may play an important role in the development and
602
progression of VKH disease. The cell mediated immune response can cause irreversible damage
603
to the fragile ocular structures and may induce neovascularization, thereby contributing to ocular
604
tissue damages in VKH. This is supported by current observations showing that biologic agents
605
specifically suppressing the cell mediated response (anti-TNF, Interferon alpha) or neovascular
606
response (anti-VEGF) are so effective in VKH management. This subject will be discussed in more
607
detail in the therapy section shown below.
608
Antigens
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Soon after the description of VKH, pigment was already thought to play an antigenic role in
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its development. Since the demonstration of hypersensitivity to uveal pigment in patients with
611
VKH disease with a skin test (McPherson and Woods, 1948), a number of studies were conducted
612
to identify the antigens as well as antibodies in patients with VKH disease (Hammer, 1971; Kudo,
613
1969; Wong et al., 1971). Compelling evidence for the central role of melanocytes in the
614
development of VKH disease came from a study reported by Lambe et al (Lambe et al., 2006). In
615
this study, a spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris
616
and Vogt-Koyanagi-Harada syndrome was induced in “double” transgenic mice. Transgenic mice
617
expressing hen egg lysozyme as a melanocyte-specific neoantigen were crossed with transgenic
618
animals expressing a CD4 T cell receptor specific for hen egg lysozyme. Depigmentation became
619
evident in the ears at 21 days of age, and as the animals grew older, it mainly affected the eyes,
620
genitalia, and the skin on the back and abdomen. This model provides further support for the
621
role of CD4+ T cells directed against melanocyte associated antigens in the pathogenesis of VKH.
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Until now, the most studied antigens implicated in the development of VKH disease are the
melanocyte-related proteins. Based on the concept that melanoma antigens are also molecules involved in
625
melanocyte-related autoimmune disease, such as VKH disease and sympathetic ophthalmia,
626
Sugita et al (Sugita et al., 1996) investigated whether the MART-1 antigen, one of the several
627
antigens identified on melanomas and melanocytes, was the target involved in VKH disease. CD8+
628
T cell clones isolated from the intraocular fluid of patients with VKH disease lysed melanocytes in 21
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a HLA-A2+-restricted manner, whereas neither CD8+ T cell clones from patients with Behcet’s
630
disease nor HTLV-1 uveitis showed this cytotoxicity. These results suggested that VKH disease
631
might be an autoimmune disease directed towards the MART-1 antigen in HLA-A2+ patients. Yamaki et al (Yamaki et al., 2000a) found that T-lymphocytes obtained from patients with
RI PT
632
VKH disease showed a significant stimulation following incubation with tyrosinase related protein
634
(TRP) 1 and TRP 2. These authors hypothesized that VKH disease was an autoimmune disease
635
directed against these two specific antigens. In addition, they also immunized Lewis rats with
636
either TRP1 or TRP2 in the presence of complete Freund’s adjuvant and developed an
637
inflammatory disease resembling VKH disease clinically and histologically (Yamaki et al., 2000b).
638
Synthetic peptides derived from tyrosinase, TRP1, TRP2 and Pmel17 were found to be specifically
639
recognized by peripheral blood mononuclear cells (PBMCs) of HLA-DRB1*0405-positive patients
640
with VKH disease (Damico et al., 2005a). These results provided evidence for the involvement of
641
tyrosinase family proteins in the development of VKH disease as a specific antigen, although the
642
precise mechanisms involved need further clarification.
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643
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633
Several other melanocyte-related antigens and other antigens have also been proposed to be involved in VKH disease, such as antigens from photoreceptors and Müller cells(Chan et al.,
645
1985), gp-100/PMel-17 (Chan et al., 1998), lens epithelium derived growth factor (LEDGF)
646
(Yamada et al., 2001b), and uveal autoantigen (UACA) (Yamada et al., 2001a). Identification of
647
antibodies against the antigen KU-MEL-1 and PAX3 in patients with VKH disease suggests that
648
these two antigens may also be involved in VKH disease (Matsuzaki et al., 2005; Otani et al.,
649
2006). Novel techniques to analyze peptide interactions with HLA class II molecules using high
650
throughput in silico methods were recently developed to identify immunogenic peptides in
652 653 654
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patients with VKH disease (Prasad and Levinson, 2005). As yet however, the causative peptide has
not yet been identified. Immune responses
As mentioned above, it has long been thought that autoimmune responses to melanin
655
may be the underlying process responsible for the lesions in multiple organs of patients with VKH
656
disease. Earlier studies demonstrated that lymphocytes from patients with VKH disease were
657
sensitized to uveal pigment as shown by various in vitro assays such as the lymphocyte 22
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transformation test (Hammer, 1971; Yuasa et al., 1975), leukocyte migration inhibition test
659
(Hammer, 1974; Sanefuji, 1974; Yuasa et al., 1975) and lymphocyte-mediated cytotoxicity test
660
(Tagwa, 1978). Studies on peripheral blood lymphocytes (PBL) performed by Maezawa et al
661
(Maezawa and Yano, 1984; Maezawa et al., 1982) identified two distinct cytotoxic lymphocytes
662
(CD4+ and CD8+) against human melanoma cells and melanocytes and these results reinforced
663
the important role of T cells in VKH disease. Analysis of surface markers on lymphocytes by laser
664
flow cytometry showed alterations in total numbers of T cells and their subpopulations (Liu and
665
Sun, 1993; Okubo et al., 1985). Norose et al(Norose et al., 1990) demonstrated a higher ratio of
666
OKT4+/8+ cells (CD4/CD8) in CSF from patients with VKH than in their peripheral blood. These
667
earlier studies suggested that certain subpopulations of T cells play a role in the development of
668
VKH disease.
SC
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669
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In the 1990’s, the wide acceptance of experimental autoimmune uveitis (especially in mice) as a model of VKH disease and extensive studies using this model have shed further light on the
671
immune responses involved in the development of VKH disease (Caspi et al., 1988; Gery et al.,
672
1986). T cells (Th1, Th17, γδ T cells and regulatory T cells), macrophages and neutrophils have
673
been extensively studied using the EAU model and their roles have been extensively reviewed
674
elsewhere (Kerr et al., 2008; Mochizuki et al., 2013). Due to the difficulty in collecting local
675
samples (such as aqueous humor or inflamed choroid) from the affected eyes, little is known
676
about the exact immune response in the human eye, though studies have demonstrated a great
677
difference in the in vitro immune responses between cells obtained from the aqueous humor as
678
compared to peripheral blood lymphocytes (Kitaichi et al., 2007). However, as a disease affecting
679
multiple organs, studies on PBLs may still shed light on the immune responses involved in this
681 682 683
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disease. This section aims to review studies regarding immune cells in VKH disease, especially T
cells and related cytokines. After priming with autoantigens (such as melanocyte-related antigens) or exogenous
peptides simulating the autoantigens (such as CMV-egH290-302 discussed in the following section),
684
naïve T cells differentiate into effector T cells: type 1 helper T (Th1) cells, Th17 cells and others. If
685
the immune responses initiated by these cells cannot be suppressed by natural regulatory T cells
686
(nTregs) generated in the thymus (Sakaguchi and Sakaguchi, 2005), autoimmune responses will
687
occur in multiple organs, including the eyes. We assayed the peripheral blood CD4+CD25high Treg 23
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cells phenotypically and functionally in patients with VKH disease with active uveitis (Chen et al.,
689
2008). CD4+CD25highTreg cells from patients with active VKH showed a significant deficiency in
690
suppressing the proliferation of CD4+CD25- T cells and in inhibiting the production of IFN-γ and
691
IL-13 by CD4+CD25- T cells, but not IL-17 production. These results suggested that the
692
development of VKH disease may partially be due to quantitatively abnormal and functionally
693
diminished CD4+CD25high Treg cells in susceptible individuals. Commodaro et al (Commodaro et
694
al., 2010) analyzed nTregs defined as CD25high Foxp3+ in patients with VKH disease and found no
695
difference in the CD4+CD25high and CD25high Foxp3+ T cells when compared to healthy controls.
696
The discrepancy may come from the different definition of nTregs in these two studies. Unlike the
697
recurrent inflammation in VKH disease, uveitis in the EAU model usually presents as a
698
self-limiting monophasic process. Earlier we found that nTregs increased significantly with the
699
development of the EAU, suggesting that increased nTregs in EAU induced in mice with normal
700
immune regulatory capacity may be partially responsible for the monophasic nature and rapid
701
regression of EAU (Sun et al., 2010). These conflicting results between VKH syndrome and the
702
EAU model further demonstrated the critical role of regulatory T cells in the maintenance of the
703
ocular immune balance and in the regression of uveitis.
SC
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704
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688
Besides our observation that regulatory T cells may be functionally defective in patients with VKH, subsequent studies have focused on a possible role for immunoregulatory cytokines in
706
the development of the disease. Commodaro et al (Commodaro et al., 2010) compared the level
707
of IL-10 (which considered as a product of T regulatory type 1 cells) and TGF-β (which is
708
considered as a product of Th3 regulatory cells) in healthy controls and in active and inactive VKH
709
patients in cell culture supernatants of peripheral blood mononuclear cells stimulated with
711 712 713
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phytohaemagglutinin. They found that TGF-β and IL-10 were increased in patients with VKH in the inactive stage of the disease and suggested that these cytokines were associated with the resolution phase of the disease. They found no differences in the frequency of regulatory T cells
in these three groups and concluded that immunoregulatory cytokines are probably more
714
important in controlling the disease. As mentioned above, the discrepancy concerning the role of
715
regulatory T cells in VKH may be due to a different definition in the terminology of regulatory T
716
cells (Chen et al., 2008). A compromised function of regulatory T cells has also been noted in
717
other immune mediated disorders such as rheumatoid arthritis and was shown to be corrected 24
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718
following anti-TNF therapy (Ehrenstein et al., 2004). The effect of anti-TNF therapy on regulatory
719
T cell populations in VKH have not yet been reported and remain an interesting subject for future
720
studies on the role of these cells in the pathogenesis of this disease. In addition to aforementioned studies on the pathology and immunopathology of VKH
RI PT
721
disease, the contribution of effector T cells to this disease has been evidenced by the dominance
723
of activated T cells in aqueous humor (Norose et al., 1994; Ohta and Yoshimura, 1998) and CSF
724
during the acute phase (Norose et al., 1990). To explain the local increase of T cells, studies have
725
been directed towards the role of apoptosis-related Fas markers on memory T cells in aqueous
726
humor and peripheral blood during VKH disease (Ohta and Yoshimura, 1998; Yang et al., 2002;
727
Yang et al., 2001) in view of the fact that the Fas-Fas-ligand system has been demonstrated to be
728
important in mediating apoptosis of immune cells and maintaining ocular immune privilege
729
(Griffith et al., 1995). These studies showed an increased expression of Fas in aqueous humor,
730
CSF and peripheral blood from patients with VKH disease (Ohta and Yoshimura, 1998). However,
731
resistance of lymphocytes to Fas-mediated apoptosis in VKH disease suggested that long-lived
732
lymphocytes may contribute to the increase of T cells and the development of uveitis (Yang et al.,
733
2002; Yang et al., 2001).
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734
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722
Th1 cells were the first subtype of T cells shown to be involved in the development of VKH disease. A number of studies addressed the role of Th1 cells and the associated cytokine profile
736
(such as IL-12, IFN-γ and IL-6) in VKH by analyzing aqueous humor, CSF and peripheral blood
737
(Andreoli and Foster, 2006; Imai et al., 2001; Miyazawa et al., 2005; Norose and Yano, 1996).
738
T-bet is considered as the critical transcriptional factor for Th1 cells and Li et al (Li et al., 2005)
739
assayed the level of T-bet, IFN-γ, IL-2 and IL-4. An up-regulated expression of T-bet and IFN-γ was
741 742 743
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found in patients with VKH disease (Li et al., 2005). These results support a role of Th1 cells in the
development of VKH disease. Th17 cells, which typically produce IL-17 by stimulation through IL-23, have also been
shown to contribute to the development of VKH disease (Chi et al., 2007; Jiang et al., 2010a).
744
Studies from our group on this subject showed an increased expression of IL-23 p19 mRNA in
745
peripheral blood mononuclear cells (PBMCs), higher levels of IL-23 in serum and supernatants of
746
PBMCs, and an increased level of IL-17 by polyclonal stimulated PBMCs and CD4+ T cells in
747
patients with active VKH (Chi et al., 2007). These results indicated that activation of the 25
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IL-23/IL-17 pathway was involved in the development of VKH disease. Further studies
749
demonstrated that production of IL-17 by polyclonal stimulated PBMCs and CD4+ T cells was
750
significantly enhanced by recombinant IL-23 and that IL-17 production by these activated cells
751
stimulated with IL-23 was significantly higher in patients with active VKH disease than in patients
752
with inactive VKH disease and in normal controls. It should be noted that many other cell types,
753
such as natural killer T (NKT) and innate lymphoid cells (ILC) can also produce IL-17. Therefore
754
levels of this cytokine do not necessarily correlate with Th17 cells numbers. An interesting
755
observation was the finding that IL-12 and IFN-γ, both of which were considered as Th1 cytokines,
756
significantly suppressed the production of IL-17 by polyclonal stimulated PBMCs and CD4+ T cells
757
(Chi et al., 2007). In addition, rIL-23, which is the growth and stabilization factor for Th17 cells,
758
enhanced IFN-γ production. These results demonstrated that both Th1 cells (IL-12/IFN-γ pathway)
759
and Th17 cells (IL-23/IL-17 pathway) were involved in the development of VKH disease.
760
Furthermore, these two cell types maybe regulated by the same cytokines.
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748
When summing up the evidence reviewed above, a hypothetical network involved in the
762
development of VKH disease can be constructed. This network is composed of different kinds of
763
effector cells, including Th1 cells, Th17 cells and nTregs. Besides cells, a number of soluble factors
764
such as cytokines, chemokines and transcription factors are also involved in the network. During
765
the development and progress of VKH disease, these factors may interact with each other
766
directly or indirectly. In turn, the network becomes more and more complicated. Our recent
767
studies provided ongoing evidence for the complicated network that may be operative in the
768
pathogenesis of VKH. Cytokines (such as IL-7 IL-21, IL-27, IL-25and IL-37) (Li et al., 2010; Wang et
769
al., 2012; Xu et al., 2014; Yang et al., 2012; Ye et al., 2015), leptin (Liu et al., 2008), osteopontin
771 772 773 774
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761
(Chu et al., 2011), 1,25-Dihydroxyvitamin D3 (Yi et al., 2011), interleukin-1 receptor-associated
kinases (IRAK) (Sun et al., 2014) and liver X receptor (Wu et al., 2014)have been demonstrated to
be involved in the development of VKH disease by regulating the IL-23/IL-17 pathway and/or Th1
cells.
It should be noted that RPE cells may also play an important role in this network, not only
775
because they are the target of immune responses, but also because they are involved in the local
776
regulation of immune homeostasis in the posterior segment of the eye. One of our studies
777
demonstrated that ARPE-19 cells, a spontaneously arisen cell line of RPE, constitutively expressed 26
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IL-17RC and IL-22R (Chen et al., 2011). Furthermore, IL-17A and IL-17F significantly enhanced the
779
production of inflammatory cytokines, such as CXCL8, CCL2, CCL20 and IL-6 by these cells (Chen
780
et al., 2011). Both IL-17A and IL-17F significantly decreased the transepithelial electrical
781
resistance (TER) of the ARPE-19 monolayer and increased the diffusion rate of fluorescein
782
isothiocyanate (FITC)-dextran. Whether the RPE layer is damaged due to the destruction of the
783
underlying choroidal capillaries thereby limiting access of necessary nutrients or due to a direct
784
autoimmune attack of RPE melanin remains to be studied.
785
Triggering factors
SC
786
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778
Though it is now accepted that VKH disease is an autoimmune disease, a triggering role of infection leading to this disease is still a widely believed concept. The acute onset and
788
self-limiting nature of symptoms, such as a slight fever, headache and fatigue during the
789
prodromal stage of VKH disease suggests a microbial infection before its onset. Epstein-Barr virus
790
(EBV) DNA has been detected in cerebrospinal-fluid from patients with Vogt-Koyanagi-Harada
791
disease using the PCR method (Usui et al., 1991), but these findings could not be confirmed by
792
other groups(Saito et al., 1993). A more direct evidence for the involvement of a virus in VKH
793
disease was the identification of EBV DNA in the vitreous from a patient with VKH disease (Bassili
794
et al., 1996). However, EBV is a ubiquitous virus in humans and a case report may not be
795
considered as formal proof of a role of EBV in VKH. A further study showed that B lymphocytes
796
from VKH patients were more susceptible to EBV activation than those from patients with other
797
uveitis entities (Minoda et al., 1999). The proposed mechanism of action suggests a resemblance
798
between virus-associated proteins and autoantigens in VKH disease. According to the
799
cross-reaction and molecular mimicry theories, the similarity between exogenous antigens
801 802
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800
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(produced by pathogenic microorganisms) and host proteins will cause an immune response
(which should be constricted to eliminate organisms) to host proteins (Oldstone, 1987). Viruses, especially retroviruses, may encode antigens that resemble host proteins. Sugita et al (Sugita et
803
al., 2006) found six amino acids with the anchor position of HLA-DRB1*0405 shared by
804
tyrosinase450-462 (peptide derived from host proteins) and cytomegalovirus envelope glycoprotein
805
H290-302 (CMV-egH290-302) (a cytomegalovirus-associated peptide). Furthermore, they isolated
806
several T cell clones that responded strongly to CMV-egH290-302 as well as to the tyrosinase450-462 27
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807
peptide (Sugita et al., 2007). These studies suggest that viral infections may trigger the
808
autoimmune response underlying VKH disease through a mechanism of molecular mimicry.
809
The need for an adjuvant in the experimental autoimmune uveitis model, which is widely accepted as a useful model for VKH disease, also supports the triggering role of infectious agents
811
in uveitis. Toll-like receptors (TLRs) are a large family of so called pattern-recognition receptors
812
(PRRs)(Kawai and Akira, 2010). Their activation by recognizing a variety of microbial immune
813
components will initiate the consequent innate immune response and shape the adaptive
814
immune responses. With the identification of TLRs in the human uveal tract (Chang et al., 2006;
815
Rodriguez-Martinez et al., 2005), the evidence for a potential role of TLRs in the pathogenesis of
816
uveitis increased rapidly (Allensworth et al., 2011; Chang et al., 2007; Fang et al., 2010). However,
817
most studies on the role of TLRs in uveitis have focused on anterior uveitis. A recent study from
818
our group showed that the macrophage expression of TLR3 and TLR4, but not TLR2, was
819
significantly increased in active VKH patients as compared to controls (Liang et al., 2015). Gene
820
variants of TLR2, TLR4, TLR8, and TLR9 were however not shown to be associated with VKH
821
disease (Fang et al., 2013; Ito et al., 2011).
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810
Other intracellular pattern recognition receptors include the so called Nucleotide-binding
823
oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2), which recognize bacterial
824
products and upon ligand binding result in an immune reaction. We recently examined the
825
expression of NODs in patients with active VKH syndrome and found a higher expression of NODs
826
on PBMCs as compared with controls (Deng et al, manuscript in preparation). Furthermore,
827
activation of NODs with their natural ligands iE-DAP or MDP markedly increased the level of
828
proinflammatory cytokines by PBMCs and DCs. Activation of NODs in DCs may also promote the
830 831 832
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829
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822
differentiation and proliferation of CD4+T cells. Taken together these findings indicate that PRRs,
such as NODs, may be involved in the pathogenesis of VKH syndrome (Deng et al. manuscript in
preparation). Further studies are required to provide new insights on the potential role of PRRs in bridging a possible role of a microbial infection in the prodromal stage of VKH disease and the
833
ensuing innate immune response leading to a chronic, adaptive autoimmune melanocyte attack
834
in multiple organs.
835
Clinical features 28
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836 837
Stage of VKH disease The most frequent complaint in patients with VKH disease is a rapid decrease in vision in one or both eyes following a transiently blurred vision. Other complaints include red eyes, eye
839
pain or orbital pain and floaters (Moorthy et al., 1995; Yang et al., 2007). According to the clinical
840
features, the course of VKH is typically classified in four consecutive stages: prodromal stage,
841
acute stage, chronic convalescent stage and chronic recurrent stage (Moorthy et al., 1995;
842
Rajendram et al., 2005; Read et al., 2001c).
843
Prodromal stage
SC
844
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838
The prodromal stage usually lasts for 1 to 2 weeks and is characterized by flu-like symptoms. Prodromal symptoms are nonspecific, including headache, tinnitus, nausea, neck and
846
back stiffness, and an abnormal sensitivity to touch of the hair (Moorthy et al., 1995; Rajendram
847
et al., 2005; Rao et al., 2010). Periorbital pain is not rare (Han et al., 2010). The auditory
848
disturbances such as tinnitus and dysacusis also occur in this stage. Rare neurologic signs,
849
including cranial nerve palsies and cerebellar or psychiatric signs have also been described
850
(Andreoli and Foster, 2006; Moorthy et al., 1995). Pleocytosis in CSF can be found by lumbar
851
puncture at this stage and this sign can last up to 8 weeks (Read et al., 2001c).
852
Acute stage
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853
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845
The acute stage begins with the occurrence of acute uveitis, typically bilateral posterior uveitis (Moorthy et al., 1995; Rajendram et al., 2005). This stage usually continues for several
855
weeks. Either choroiditis or chorioretinitis of a nongranulomatous nature is the most prominent
856
finding within the first 2 weeks (Rao et al., 2010; Yang et al., 2007). The anterior segment is
858 859
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857
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854
spared from inflammation during these 2 weeks, though mild anterior chamber flare can be
observed in some patients. In Chinese patients with VKH disease, we define this stage as the
posterior uveitis stage because inflammation is limited to the posterior segment of the eye (Yang
860
et al., 2007). A sudden decrease in vision in both eyes is the most often mentioned complaint at
861
this stage. The visual acuity varies from light perception to more than 20/40 (Rubsamen and Gass,
862
1991; Yang et al., 2007). In the majority of patients, both eyes are affected simultaneously.
863
According to observations, the interval from uniocular to binocular involvement ranged from 1 to 29
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2 weeks, mostly occurring within 7 days (Chi et al., 2007; Moorthy et al., 1995; Rajendram et al.,
865
2005). Unilateral ocular involvement in patients with presumed VKH disease has been noted
866
during a disease follow up of 16 years (Usui et al., 2009). Multiple exudative retinal detachment
867
(ERD) (Fig 3), optic disc swelling and thickening of the posterior choroid with slight involvement
868
of vitreous body are the typical signs at the acute stage (Moorthy et al., 1995; Rajendram et al.,
869
2005; Yang et al., 2007). ERD, typically multiple and localized to the posterior pole and/or the
870
midperiphery, is present in over 85% of cases (da Silva et al., 2009a; Keino et al., 2006; Yang et al.,
871
2007). A multicenter study including different ethnic groups of patients with bilateral acute VKH
872
uveitis has shown that bilateral ERD during the acute stage is a highly specific sign for this entity
873
(Rao et al., 2010). Optic disk hyperemia or edema can be found in 69% to 87% of cases
874
(Bordaberry, 2010; Yang et al., 2007). The occurrence of disk edema has been shown to be
875
associated with age and disc morphology (Nakao et al., 2012). Furthermore, the optic disc edema
876
may lead to visual field defects in patients by ischemic damage (Nakao et al., 2012; Nakao et al.,
877
2009). Round, white-yellowish lesions of variable size, located in the posterior or midperipheral
878
fundus (Moorthy et al., 1995) and choroidal folds in the posterior pole are also common signs
879
during the acute stage (Wu et al., 2007; Zhao et al., 2009).
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864
Involvement of the anterior segment ensues if the disease is not well controlled,
881
presenting as mild to moderate anterior uveitis with a nongranulomatous nature. This stage is
882
defined as the anterior uveitis stage in our classification (Yang et al., 2007). Signs suggesting
883
granulomatous inflammation, such as mutton fat keratic precipitates on the corneal endothelial
884
surface or Koeppe and Busacca nodules in the iris are rarely present (Yang et al., 2007).
885
Occasionally, manifestations resembling acute angle closure glaucoma, such as a shallow anterior
887 888
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886
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880
chamber and increased IOP, may be present in certain individuals because of ciliary body edema
secondary to the inflammation (Yang et al., 2011; Yao et al., 2013).
Chronic (convalescent) stage
889
According to studies reported previously, a chronic convalescent stage occurs several
890
weeks after the acute stage and continues for months or even years (Rajendram et al., 2005).This
891
stage is characterized by signs of depigmentation in integumentary and/or uveal tissue. Sunset
892
glow fundus is the most common sign resulting from depigmentation of the choroid at this stage 30
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(Yang et al., 2007). It has been shown to be very specific to VKH disease in the setting of chronic
894
bilateral uveitis and is useful for its diagnosis (Rao et al., 2010). Nummular chorioretinal scars
895
presenting as well-defined oval or round areas in the midperiphery of the fundus is another
896
common sign for VKH disease (Rao et al., 2010; Yang et al., 2007). Poliosis of the eyebrows or
897
eyelashes, alopecia and vitiligo are the most common signs of depigmentation occurring during
898
the chronic stage (Rao et al., 2010; Yang et al., 2007). Other signs of disturbance in pigmentation
899
include the so called Sugiura sign (depigmented limbus), peripheral iris depigmentation and RPE
900
clumping/migration (Attia et al., 2007; Friedman and Deutsch-Sokol, 1981; Rao et al., 2010). The
901
Sugiura sign is rarely seen in other populations than from Japanese descent (Friedman and
902
Deutsch-Sokol, 1981). RPE clumping/migration are among the most common signs in the chronic
903
stage of VKH disease (Rao et al., 2010).
904
Chronic recurrent stage
SC
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905
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893
The chronic recurrent stage is characterized by a mild panuveitis with recurrent episodes of anterior uveitis. This stage is usually considered to be the result of inadequate or delay of
907
treatment with corticosteroids for the disease (Moorthy et al., 1995; Rajendram et al., 2005).
908
With the recurrence of anterior uveitis, the inflammation gradually changes from
909
nongranulomatous to a granulomatous nature. Mutton fat keratic precipitates on the corneal
910
endothelial surface and flare and cells in the anterior chamber are the typical features of this
911
stage. Koeppe and Busacca nodules in the iris are not uncommon in the recurrent stage (Rao et
912
al., 2010; Yang et al., 2007). Iris atrophy and depigmentation may also be seen (Attia et al., 2007;
913
Moorthy et al., 1995). However, recurrent posterior uveitis with exudative retinal detachment,
914
optic disc swelling and vitritis are less common (Andreoli and Foster, 2006; Yang et al., 2007).
916 917
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906
Most of the ocular complications, such as cataract, glaucoma, choroidal neovascular
membranes and subretinal fibrosis develop during this stage. Complicated cataract is the most
frequent complication and subretinal fibrosis is the most severe complication (Moorthy et al.,
918
1995; Yang et al., 2007). A recent study demonstrated that VKH disease was the third primary
919
specific type of uveitis causing inflammatory CNV in China (Wu et al., 2015).
920 921
The rate of ocular complications has been shown to be associated with the number of recurrences of inflammation and to the duration of the disease (Read et al., 2001c). 31
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922 923
Staging system in the Chinese population The staging system of VKH disease as discussed above has now been widely accepted, because more consideration has been given to the process of VKH disease as well as the
925
accompanying immune response. This staging system embodies the natural history of VKH
926
disease. However, the boundary between the chronic convalescent stage and the chronic
927
recurrent stage is still obscure, especially for patients in the chronic recurrent stage only showing
928
anterior nongranulomatous uveitis. Therefore, we would like to propose an alternative staging
929
system that also includes 4 stages but which emphasizes the evolutionary processes based on a
930
study of 410 consecutive Chinese VKH patients. It consists of a prodromal stage (about 1 or 2
931
weeks before uveitis onset), a posterior uveitis stage (about 2 weeks after uveitis onset), an
932
anterior uveitis stage (from 2 weeks to 2 months after uveitis onset) and a recurrent
933
granulomatous anterior uveitis stage (more than 2 months after uveitis onset). We believe that
934
our staging system is much simpler for diagnosis. In addition, this system pays more attention to
935
the dynamic changes in the anatomical location in the eye and the nature of the inflammation.
936
The intraocular inflammation observed in Chinese patients with VKH proceeds from the posterior
937
segment to the anterior segment and from a nongranulomatous to a recurrent or chronic
938
granulomatous nature if the disease was not properly controlled therapeutically (Yang et al.,
939
2007). It is noteworthy that not all patients with VKH disease go through all 4 stages. Appropriate
940
management can halt the disease at either the posterior uveitis stage or the anterior uveal
941
involvement stage (Chee et al., 2007; Rajendram et al., 2005; Yang et al., 2007).
942
Complications
944 945 946 947
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943
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Approximately half of the patients and half of the eyes develop at least one complication
(Read et al., 2001c). Cataract, glaucoma, subretinal fibrosis and choroidal neovascularization are
the most common complications seen in VKH disease (Moorthy et al., 1995; Ozdal et al., 2014;
Read et al., 2001c).
Recurrent anterior segment inflammation and prolonged systemic corticosteroid therapy
948
are considered as another risk factor for complicated cataract, which is the most common
949
complication. According to previous studies, cataract occurs in 10.5% to 42% of eyes (Chi et al.,
950
2007; Moorthy et al., 1995; Moorthy et al., 1994; Ohno et al., 1988; Ozdal et al., 2014; Read et al., 32
ACCEPTED MANUSCRIPT
2001c). Read et al (Read et al., 2001c) proposed that the great difference in the rate of cataract
952
may come from the definition of cataract employed among studies, because there was no
953
description of the type of cataract in these studies except their own studies (Moorthy et al., 1994;
954
Read et al., 2001c). We speculate that the proportion of patients which are at different stages
955
may also influence the rate of complicated cataract within a study. The series including more
956
patients at the chronic recurrent stage will thus have a higher rate of complicated cataract. The
957
rate of cataract in VKH children ranges from 23.9% to 61.5% (Abu El-Asrar et al., 2008; Rathinam
958
et al., 1998; Soheilian et al., 2006; Tabbara et al., 1998).
SC
959
RI PT
951
Glaucoma develops in 6% to 45% of eyes (Nakao et al., 2009). The incidence of glaucoma in VKH children is similar to that in the whole population of VKH patients, ranging from 22% to 46%
961
(Rathinam et al., 1998; Tabbara et al., 1998). Forster et al (Forster et al., 1993) analyzed 16
962
patients with VKH disease accompanied by complicated glaucoma and found that nine (56.3%)
963
had open-angle glaucoma and seven (43.7%) had angle-closure secondary to pupillary block.
964
M AN U
960
Subretinal fibrosis and choroidal neovascularization are the complications leading to severe vision loss. Lertsumitkul et al (Lertsumitkul et al., 1999) reported that subretinal fibrosis
966
developed in 40% of 75 patients and choroidal neovascularization in 14.7% of cases. Our results
967
in a Chinese population showed that less than 2% of all 819 eyes investigated were complicated
968
by subretinal fibrosis (Yang et al., 2007). A recent analysis for clinical characteristics in Turkish
969
VKH patients also demonstrated a lower rate of 2% for subretinal fibrosis (Ozdal et al., 2014).
970
Therefore, there is a difference in the rate of subretinal fibrosis depending on the ethnicity. In
971
addition, long standing and recurrence of inflammation are also considered as a risk factor
972
associated with subretinal fibrosis and neovascularization (Chi et al., 2007; Kuo et al., 2000).
974 975 976
EP
AC C
973
TE D
965
Patients who had a disease duration of ≥12 months at presentation were more likely to have
subretinal neovascularization or fibrosis than patients with a disease duration of ＜12 months at the time of presentation (Bykhovskaya et al., 2005; Kuo et al., 2000). In children with VKH disease,
the incidence of subretinal neovascular membranes has been reported to be as high as 54% to 70%
977
(Soheilian et al., 2006; Tabbara et al., 1998). These findings are much higher as compared to a
978
recent study whereby subretinal neovascular membranes occurred in 4.3% and subretinal fibrosis
979
occurred in 2.2% of 46 eyes of children with VKH (Abu El-Asrar et al., 2008).
980
Other complications such as cystoid macular edema (Bykhovskaya et al., 2005; Rutzen et 33
ACCEPTED MANUSCRIPT
al., 1995), band-shaped keratopathy (Yang and Sun, 2011), and visual field defects have also been
982
reported (Nakao et al., 2012; Nakao et al., 2009).
983
Ancillary tests
984
Fluorescein angiography (FA)
985
RI PT
981
FA is a helpful ancillary test for VKH disease and it has been described extensively (da Silva et al., 2009a; Moorthy et al., 1995; Rajendram et al., 2005). Briefly, in the acute stage of VKH
987
disease, FA (Fig 4) reveals numerous punctate hyperfluorescent dots at the level of the RPE. In
988
the late phase of the angiogram, staining of the subretina surrounding the hyperfluorescent dots
989
and pooling of the dye in areas of an exudative retinal detachment are noted. Optic disc
990
hyperfluorescence and leakage can also be seen frequently. Window defects caused by atrophic
991
chorioretinal scars in the late phase of the angiogram are always located in the midperipheral
992
area, which is common in VKH disease and rarely observed in other uveitis entities except for
993
sympathetic ophthalmia. FA during the late stage of VKH reveals nonspecific window defects and
994
blockade due to retinal pigment epithelium damages. FA is also helpful for identifying choroidal
995
neovascularization and subretinal fibrosis.
996
Ultrasonography
TE D
M AN U
SC
986
As a noninvasive ancillary test, B-scan ultrasonography is useful for the diagnosis of VKH
998
disease in the acute stage (Forster et al., 1990). The echographic manifestations of VKH disease
999
include diffuse, low-to-medium reflective thickening of the posterior choroid; serous
1001 1002 1003 1004
detachments of the retina located in the posterior pole or inferiorly; some vitreous opacities with
AC C
1000
EP
997
no posterior vitreous detachment; and posterior thickening of the sclera or episclera. Recently,
high-resolution ultrasonography (20-MHz) has been shown to be helpful in detecting subclinical
ERD and in monitoring response to treatment (Khairallah et al., 2007b). Though the echographic
features of VKH disease are distinct in the context with the history and other physical findings, it
1005
is important to differentiate it from posterior scleritis, benign reactive lymphoid hyperplasia of
1006
the uvea and malignant choroidal melanoma (Moorthy et al., 1995).
1007
Lumbar puncture
1008
According to Sugiura’s diagnostic criteria, lumbar puncture for examining the pleocytosis is 34
ACCEPTED MANUSCRIPT
required, because pleocytosis was found in 80% of patients within 1 week and in 97% of patients
1010
within 3 weeks of the onset of inflammation (Sugiura, 1976a, 1978). A recent study has
1011
demonstrated that more than 70% of acute and chronic VKH patients had pleocytosis in Japan
1012
(Yamaki et al., 2005). Clinically, this procedure is rarely used due to its invasive nature. Analysis of
1013
T lymphocyte subpopulations (CD3+, CD4+ and CD4+ CD45RO+) showed that the profiles were
1014
identical for CSF and aqueous humor but that they differed from the cells found in blood,
1015
suggesting that analysis of CSF may reflect the local immunological reaction at sites (uvea and
1016
meninges) affected by the disease (Kitaichi et al., 2007).
1017
Indocyanine green angiography (ICGA)
SC
RI PT
1009
ICGA has been shown to be one of the most useful tests to observe the evolution of
1019
choroidal inflammatory involvement and to monitor the efficacy of treatments (Bouchenaki and
1020
Herbort, 2001). A set of ICGA signs in VKH disease has been systemically reviewed for the
1021
follow-up of the choroidal inflammation (Bouchenaki and Herbort, 2001; Herbort et al., 2007)
1022
(Fig 4). Early choroidal perfusion in homogeneity has been considered as an important and
1023
specific sign in VKH disease, although there are some controversies (Miyanaga et al., 2010). Early
1024
hyperfluorescent stromal vessels (Fig 4), which indicate severe choroidal stromal inflammatory
1025
vasculopathy, may be used as a semiquantitative parameter by counting the number of these
1026
vessels. Hypofluorescent dark dots, which are thought to correspond to choroidal granulomas,
1027
are the most readily recordable angiographic sign. Other signs include fuzzy or lost vascular
1028
patterns of large stromal vessels seen in the intermediate to late angiographic phases and disc
1029
hyperfluorescence, which indicates very severe disease. Diffuse late choroidal
1030
hyperfluorescenceis also a consistent sign seen by ICGA in VKH. It has been shown that ICGA can
1032 1033
TE D
EP
AC C
1031
M AN U
1018
be used to detect subclinical inflammation in the choroid which cannot be found clinically in early stages or after systemic therapy (Kawaguchi et al., 2010). ICGA signs such as dark dots, fuzzy or
lost vascular and diffuse choroidal hyperfluorescence may indicate choroidal inflammation
1034
(Bouchenaki and Herbort, 2011; Herbort et al., 2007).
1035
Optical coherence tomography (OCT)
1036 1037
OCT has been widely used for evaluating the ERD present in the early stage of VKH disease. With the increase of resolution, OCT reveals more details of ERD and helps to formulate a new 35
ACCEPTED MANUSCRIPT
hypothesis concerning the cause of ERD (Fig 3). Studies have demonstrated two patterns of
1039
serous retinal detachment: true serous retinal detachment and intraretinal fluid accumulation
1040
(Ishihara et al., 2009; Lee et al., 2009). Subretinal septa, which divide the subretinal space of ERD
1041
into several compartments, may represent fibrin membranes resulting from the inflammatory
1042
reaction. These septa may be responsible for multilobular dye pooling revealed by FA (Yamaguchi
1043
et al., 2007). OCT has also been used to study the choroidal folds, folds of RPE, Bruch’s
1044
membrane, and external limiting membrane in VKH disease (Gupta et al., 2009; Hashida et al.,
1045
2014; Mili-Boussen et al., 2013; Sakata et al., 2014; Tsuboi et al., 2015; Vasconcelos-Santos et al.,
1046
2010; Wu et al., 2007; Zhao et al., 2009). Most recently, enhanced depth imaging optical
1047
coherence tomography (EDI-OCT) has been introduced to evaluate the thickness of the choroid
1048
and retina in VKH (Hashizume et al., 2014; Invernizzi et al., 2015; Margolis and Spaide, 2009; Park
1049
et al., 2013; Tagawa et al., 2015; Takahashi et al., 2014). Studies showed that the choroidal
1050
thickness was markedly increased in the acute phase of VKH disease and decreased quickly after
1051
systemic corticosteroid treatment or in the convalescent stage of VKH disease. Obviously, OCT is
1052
becoming a useful tool for evaluating the severity of VKH disease and to monitor the response to
1053
treatment.
1054
Other ancillary tests
SC
M AN U
TE D
1055
RI PT
1038
Ultrasound biomicroscopy (UBM) is helpful to evaluate changes in the anterior segment during VKH disease. Usually, no substantial changes can be detected by UBM in the posterior
1057
uveitis stage and in the remission stage (Wada et al., 2002). During the anterior uveal
1058
involvement stage and the recurrent granulomatous uveitis stage, a shallow anterior chamber,
1059
ciliochoroidal detachment, thickened and swollen ciliary body, anterior rotation and anterior
1061 1062
AC C
1060
EP
1056
bowing of the iris may be visualized by UBM (Gohdo and Tsukahara, 1996; Yang et al., 2007).
Laser flare photometry (LFCM) has been designed to provide an objective measurement for the evaluation of aqueous flare and cells. With the use of LFCM we have been able to show that
1063
recurrent VKH patients displayed a more striking and long-lasting breakdown of the blood–
1064
aqueous barrier and more severe inflammation than initial-onset VKH patients (Fang et al., 2008).
1065
Electroretinography has also been used to evaluate the macular and retinal function in VKH
1066
patients (da Silva et al., 2009b; Yang et al., 2008). Our recent studies have shown a severe 36
ACCEPTED MANUSCRIPT
decrease in visual acuity and diffuse mfERG abnormalities in patients with VKH disease before
1068
treatment, suggesting severe damage of the macular area. The parameters of mfERG (N1 and P1
1069
waves) gradually improved following treatment, indicating that mfERG may be a useful tool to
1070
monitor therapy in patients with VKH disease (Yang et al., 2008). Autofluorescence, magnetic
1071
resonance imaging and other ancillary tests can also be helpful for diagnosis and follow-up of the
1072
disease (Johnston and Teitelbaum, 1990; Koizumi et al., 2010; Vasconcelos-Santos et al., 2010)
1073
(Fig 3). Multi-spectral image (MSI) is a novel non-invasive tool for revealing the morphological
1074
changes of the fundus. Our recent investigation showed a significant higher percentage of
1075
morphological alternations (depigmentation, migration and clumping of pigment, macular
1076
depigmentation and/or hyperpigmentation) discovered by MSI as compared with those detected
1077
by FFA, OCT and FP (manuscript in preparation).
1078
Therapy
SC
M AN U
1079
RI PT
1067
Rapid and aggressive therapy using systemic corticosteroids should be installed once the diagnosis is made. The majority of VKH patients in the acute stage respond to the treatment with
1081
corticosteroids and gradually tapered systemic corticosteroids should be maintained for several
1082
months to prevent progression into the chronic stage and to prevent future recurrences.
1083
Accumulating evidence has suggested that prescription of immunosuppressive agents at the
1084
acute stage of VKH disease is associated with better visual outcomes (Abu El-Asrar et al., 2013;
1085
Urzua et al., 2015). For patients at the chronic stage, immunosuppressive agents are required to
1086
control the inflammation. Recently developed biologic agents have been shown to be effective
1087
for refractory VKH disease and for treating neovascularization occurring in the chronic stage
1088
(Busanyova et al., 2013; Cordero-Coma et al., 2013; Wu et al., 2009; Zmuda et al., 2013). Topical
1090 1091
1092 1093
EP
AC C
1089
TE D
1080
steroids, cycloplegics and mydriatics are recommended to control the associated anterior uveitis (Moorthy et al., 1995). Possible side-effects of all medications should be closely monitored during follow-up.
Corticosteroids Early and aggressive systemic corticosteroids are still the mainstay of treatment for acute
1094
VKH disease (Lai et al., 2009; Moorthy et al., 1995; Read et al., 2006; Rubsamen and Gass, 1991).
1095
The average initial dose of corticosteroids is 80 to 100 mg of oral prednisone per day and 37
ACCEPTED MANUSCRIPT
maintained for 2-4 weeks, although a dose of more than 200 mg has been recommended for
1097
severe cases (Hayasaka et al., 1982; Moorthy et al., 1995; Rubsamen and Gass, 1991). The initial
1098
high dose of corticosteroids can be administered either orally or intravenously. Some
1099
investigators reported that the initial treatment with pulsed high dose intravenous
1100
corticosteroids rapidly improved serous detachment (Sasamoto et al., 1990; Yamanaka et al.,
1101
2002).The effect of two routes of administration of corticosteroids (orally or intravenously
1102
followed by an oral taper) have been compared on the outcome of VKH disease and showed no
1103
difference concerning the long-term visual acuity recovery and ocular complications between the
1104
two groups(Read et al., 2006). Therefore, oral administration may be the first choice, except for
1105
severe cases. Following the initial high dose, systemic corticosteroid treatment should be tapered
1106
off gradually, usually maintaining treatment for at least 6 months (Lai et al., 2009; Moorthy et al.,
1107
1995; Read et al., 2006), although a longer duration of 45 months has also been reported (Fujioka
1108
et al., 1980). Patients who received systemic corticosteroid treatment for less than 6 months have
1109
been demonstrated to be more likely to have a recurrence and more severe vision loss than those
1110
who received treatment for more than 6 months (Lai et al., 2009). As for the tapering course,
1111
there is still no standard dosage. A study comparing the effect of high- or medium-dose systemic
1112
corticosteroid treatment during the early 4-month treatment phase demonstrated that a dose of
1113
0.36 mg/kg/day is not sufficient to suppress subclinical progression whereas a dose as high as
1114
0.75 mg/kg/day was required to control the disease (Kawaguchi et al., 2010). For patients who
1115
cannot tolerate systemic corticosteroids, triamcinolone acetonide and dexamethasone
1116
intravitreal implants have been shown to improve visual acuity and serous retinal detachment
1117
and may thus be an alternative tool in the treatment (Andrade et al., 2004; Burkholder et al.,
1119 1120 1121
SC
M AN U
TE D
EP
AC C
1118
RI PT
1096
2015; Cao et al., 2014; Karacorlu et al., 2006; Latronico et al., 2015; Zarranz-Ventura et al., 2014). In our clinic, VKH patients are treated with oral corticosteroids (initial dosage, 1.0 –1.2
mg/kg per day), often in combination with immunosuppressive agents (see below) (Yang et al., 2007). The corticosteroids dosage is tapered gradually and treatment is continued for at least 10
1122
months. Corticosteroid eye drops and cycloplegic agents are used for cases with anterior
1123
chamber reaction. Local treatment with eye drops is usually continued for 2 to 4 weeks.
1124
Prolonged corticosteroid eye drops are given to chronic or refractory VKH patients, or patients
1125
with macular edema (ME). Intravitreal triamcinolone (IVTA), according to our experience, reduces 38
ACCEPTED MANUSCRIPT
1126
ME and improves vision, but cataract and glaucoma are frequent complications. Corticosteroid
1127
implants are currently not commercially available in China.
1128
Immunosuppressive agents For those patients presenting at the chronic phase or with chronic recurrent disease, and
RI PT
1129
who are intolerant or resistant to corticosteroids, immunosuppressive agents (such as
1131
cyclosporine, azathioprine, methotrexate, chlorambucil and cyclophosphamide) are employed to
1132
suppress the ocular inflammation (Andreoli and Foster, 2006; Rao, 2006; Yang et al., 2007). One
1133
of the most extensive studies on the use of immunosuppressive agents described the use of
1134
cyclosporine A (CsA) in the treatment of VKH (Nussenblatt et al., 1985; Vitale et al., 1996;
1135
Wakefield et al., 1990). Later studies compared the efficacy of azathioprine and cyclosporine for
1136
VKH disease in combination with corticosteroids and showed that CsA seems to be a better
1137
glucocorticoid-sparing agent than azathioprine (Cuchacovich et al., 2010). Our own in vitro
1138
studies showed an inhibitory effect of CsA and corticosteroids on the production of IFN-γ and
1139
IL-17 by T cells obtained from patients with VKH disease (Liu et al., 2009). Either dexamethasone
1140
or prednisone do not completely inhibit the production of IL-17 and IFN-γ. However, low doses of
1141
CsA (3–5 mg/kg per day) in combination with low doses of corticosteroids can decrease IL-17 and
1142
IFN-γ more effectively (Liu et al., 2009). These results may partially explain the effect of CsA for
1143
treatment of VKH disease. Azathioprine, an inhibitor of purine synthesis, has also been shown to
1144
be effective for the treatment of VKH disease, usually in combination with corticosteroids
1145
(Cuchacovich et al., 2010; Kim and Yu, 2007; Pacheco et al., 2008). Aggressive triple
1146
immunosuppressive agent therapy (oral prednisolone, azathioprine and cyclosporine) has been
1148 1149 1150 1151
M AN U
TE D
EP
AC C
1147
SC
1130
reported for the treatment of VKH disease and resulted in a rapid remission in all patients and
helped in preventing recurrences (Agarwal et al., 2006). Taken together, the use of these additional immunosuppressive agents has proven to be a great complement for corticosteroids in controlling the inflammation in VKH disease. The discussion nowadays among uveitis specialists is whether immunosuppressive agents
1152
should be employed as a first-line therapy for VKH disease. Paredes et al (Paredes et al., 2006)
1153
reported the results of a series of 8 patients with VKH disease who received prompt
1154
immunosuppressive agents with or without systemic corticosteroids and compared their 39
ACCEPTED MANUSCRIPT
treatment outcomes with those of another group of 5 patients treated with prolonged steroid
1156
therapy with or without the delayed addition of immunosuppressive agents. They concluded that
1157
patients treated initially with immunosuppressive agents had a better visual outcome than those
1158
who received a prolonged treatment with corticosteroids. Other recent studies confirmed the
1159
benefit of first-line immunomodulatory therapy for improving visual acuity and controlling
1160
inflammation (Abu El-Asrar et al., 2013; Urzua et al., 2015). Our data also indicate that first-line
1161
immunomodulatory therapy is associated with the better visual outcome and a lower frequency
1162
of recurrence (not published). The studies described above are uncontrolled and prospective
1163
randomized clinical trials are needed to validate the various treatment options for VKH (Rao,
1164
2006).
SC
In our clinic, systemic corticosteroid treatment is combined with Cyclosporine or
M AN U
1165
RI PT
1155
chlorambucil in those patients who had severe exudative retinal detachment (Yang et al., 2007).
1167
Treatment is often continued for one year. The initial dosage of cyclosporine is 3 to 5 mg/kg per
1168
day and chlorambucil is usually used at 0.1 mg/kg per day. The dosages of corticosteroids and
1169
other immunosuppressive agents were adjusted according to severity of the uveitis or in case of
1170
the occurrence of side effects. White blood cell counts, kidney and liver functions were regularly
1171
monitored.
1172
Biologic agents
Infliximab, a chimeric (mouse–human) immunoglobulin monoclonal antibody to tumor
EP
1173
TE D
1166
necrosis factor alpha (Fig 5), has been shown to be effective in the treatment of uveitis, especially
1175
refractory recurrent or corticosteroid-resistant uveitis (Cordero-Coma et al., 2013; Zmuda et al.,
1176 1177 1178 1179
AC C
1174
2013). It can bind both soluble and membrane bound TNF-α, neutralizing the biologic activity of TNF-α which has been implicated in the pathogenesis of uveitis (Santos Lacomba et al., 2001). Several case reports describing the treatment of VKH disease with infliximab have been reported
(Table 7) (Chen et al., 2008; Kahn et al., 2006; Khalifa et al., 2010; Niccoli et al., 2009; Suhler et al.,
1180
2009; Zmuda et al., 2013). The efficacy of Infliximab for VKH disease seems promising, especially
1181
for refractory recurrent or corticosteroid-resistant uveitis.
1182 1183
Interferon α2a (IFN-α2a), an agent that has both immunomodulatory and antiviral properties, has been successfully used in the treatment of severe and refractory uveitis 40
ACCEPTED MANUSCRIPT
associated with Behcet’s disease (Touitou et al., 2007). However, care should be taken when
1185
employing IFN-α2a for the treatment of VKH disease, in view of the observation of
1186
interferon-induced VKH-like disease in patients treated with this drug for chronic viral hepatitis C
1187
(Al-Muammar et al., 2010; Papastathopoulos et al., 2006; Soma et al., 2011). Touitou et al
1188
(Touitou et al., 2007) believe that it is still a good option for VKH patients without HCV infection
1189
because of the observed spectacular efficacy of IFN-α2a treatment (Touitou et al., 2007). As yet,
1190
these findings have not been confirmed by others.
Two other biologic agents known for controlling inflammation have also been reported for
SC
1191
RI PT
1184
the treatment of refractory uveitis. Adalimumab, a biologic agent targeting TNF (Fig 5), was also
1193
reported to be effective for the treatment of VKH disease in a patient with refractory recurrent
1194
uveitis (Diaz Llopis et al., 2007; Jeroudi et al., 2014). Rituximab, a human–murine chimeric
1195
monoclonal antibody targeting CD20 (Fig 5), has also been reported to be effective in patients
1196
with VKH disease unresponsive to TNF blockers (Dolz-Marco et al., 2011; Umran and Shukur,
1197
2015).
M AN U
1192
Anti-VEGF agents have been widely used to control ocular neovascularization and macular
1199
edema (Rodrigues et al., 2009). Bevacizumab, an anti-VEGF agent (Fig 5), has been reported to be
1200
effective for controlling neovascular membrane formation and improving visual acuity (Raffa and
1201
Bawazeer, 2009; Wu et al., 2009). Arevalo et al (Arevalo et al., 2011) examined 22 consecutive
1202
patients with inflammatory choroidal neovascularization which were treated with intravitreal
1203
bevacizumab (1.25 or 2.5mg) after the underlying uveitic condition was controlled and found that
1204
intravitreal bevacizumab provided stability or improvement in best-corrected visual acuity at 24
1205
months. A retrospective multicenter study including 81 patients confirmed efficacy of
1207 1208 1209
EP
AC C
1206
TE D
1198
bevacizumab for inflammatory ocular neovascularization refractory to standard therapy (Mansour et al., 2012). Combination therapy of intravitreal injection of bevacizumab and
triamcinolone acetate for recurrent inflammatory choroidal neovascularization has also been reported recently (Pai et al., 2012; Reibaldi et al., 2014).The studies mentioned above did not
1210
include VKH patients. A novel anti VEGF drug, conbercept (Fig 5), that has been approved by the
1211
China Food and Drug Administration for the treatment of neovascular AMD in China was recently
1212
used in our clinic to treat macular edema and choroidal neovascularization in patients with VKH
1213
disease. Our results demonstrated that anti-VEGF therapy had a significant effect in controlling 41
ACCEPTED MANUSCRIPT
1214
the edema and choroidal neovascularization and improving BCVA (unpublished data).
1215
Management of VKH in special groups
1216
In children, the mainstay treatment for acute VKH disease is high-dose corticosteroids. Considering the side effects of prolonged systemic corticosteroid therapy, especially growth
1218
retardation, successful treatment of children with VKH disease with immunosuppressive agents
1219
such as methotrexate, cyclosporine, azathioprine and cyclophosphamide has recently been
1220
reported (Abu El-Asrar et al., 2008; Martin et al., 2010; Soheilian et al., 2006; Tabbara et al.,
1221
1998). Biologic agents have also been reported in the treatment of children with VKH and
1222
showed significant therapeutic effectiveness (Jeroudi et al., 2014; Umran and Shukur, 2015).
1223
These reports are mainly based on retrospective studies and case reports and to date no
1224
randomized clinical trials have been published. There is still no standard regimen for these
1225
immunosuppressive agents in the treatment for pediatric VKH disease, because VKH is a
1226
relatively rare cause of uveitis in children. It should be noted that collaboration with a
1227
pediatrician is critical when high-dose corticosteroids and/or immunosuppressive agents are
1228
prescribed.
SC
M AN U
High-dose corticosteroids have also been reported to be effective for VKH disease during
TE D
1229
RI PT
1217
pregnancy. These patients who had healthy deliveries received a treatment of high-dose
1231
corticosteroids in the second and third trimesters of pregnancy (Friedman et al., 1980; Miyata et
1232
al., 2001; Tien and Teoh, 2009). However, spontaneous abortions and a lower birth-weight have
1233
been reported (Doi et al., 2000; Steahly, 1990), although the relationship between these events
1234
and corticosteroid therapy was not established.
1236 1237
AC C
1235
EP
1230
Management of complications Ocular complications usually require additional management beyond systemic therapy.
Cataract surgery should be performed 3 months after complete resolution of inflammation
1238
(Moorthy et al., 1994). Steroid prophylaxis from 4 days to 2 weeks before and after surgery is
1239
necessary (Ganesh et al., 2004; Meacock et al., 2004; Quek et al., 2011). Ganesh et al (Ganesh et
1240
al., 2004) observed a lower incidence of synechiae and posterior capsule opacification in patients
1241
receiving phacoemulsification when compared to those who received extra-capsular cataract 42
ACCEPTED MANUSCRIPT
extraction, suggesting the advantages of phacoemulsification over extra-capsular cataract
1243
extraction in complicated cataract. These advantages may partially result from the fact that the
1244
blood-aqueous barrier is less affected following phacoemulsification and surface-modified
1245
intraocular lens implantation. However, Quek et al (Quek et al., 2011) failed to find a difference in
1246
outcome between VKH eyes that underwent extracapsular cataract extraction by manual nuclear
1247
expression and eyes that underwent phacoemulsification. Posterior segment complications are
1248
the main determinants for postoperative visual acuity in VKH (Ganesh et al., 2004; Quek et al.,
1249
2011). If cystoid macular edema occurs, supplemental treatment with topical non-steroidal
1250
anti-inflammatory drugs should be considered (Quek et al., 2011).
SC
RI PT
1242
1251
Different strategies should be considered for glaucoma caused by VKH disease, because several mechanisms including blocking the trabecular meshwork by inflammatory cells, damage
1253
of the trabecular meshwork, peripheral anterior synechiae, pupillary block due to extensive
1254
posterior synechiae and corticosteroid-induced ocular hypertension may be involved (Forster et
1255
al., 1993; Moorthy et al., 1995; Read et al., 2001c). In addition to medications, surgical
1256
intervention including laser iridotomy, surgical iridectomy, trabeculectomy and Molteno
1257
implantation have been used to treat glaucoma in this patient group (Bykhovskaya et al., 2005;
1258
Forster et al., 1993). It should be noted that a subgroup of VKH disease presenting with a bilateral
1259
increased IOP responds well to corticosteroids but not to anti-glaucoma treatment (Yang et al.,
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2011).
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The risk of subretinal neovascularization or fibrosis can be reduced by 82% with oral
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corticosteroid treatment (Bykhovskaya et al., 2005). In addition to the anti-VEGF therapy, laser
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photocoagulation (Wu et al., 2009), photodynamic therapy with verteporfin (Farah et al., 2002;
1264 1265 1266 1267
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Nowilaty and Bouhaimed, 2006), and surgical excision (Foster et al., 2000) have also been reported for the treatment of subretinal fibrosis.
Prognosis
The visual prognosis of VKH disease is generally good in case of prompt diagnosis and
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appropriate treatment with corticosteroids and immunosuppressive agents (Damico et al., 2005b;
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Moorthy et al., 1995; Rajendram et al., 2005; Read et al., 2001b; Yang et al., 2007). Ozdal et al
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(Ozdal et al., 2014) reported that 73.4% of 32 Turkish VKH patients (10 complete, 16 incomplete,
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6 probable; 16 at acute stage, 16 at chronic stage) achieved BCVA ≥20/40. In 67 (134 eyes) 43
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Singapore VKH patients, about 74% achieved BCVA ≥20/40 (Chee et al., 2009). In 87 (174 eyes )
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Saudi Arabia VKH patients, including 53 patients with initial-onset acute VKH disease and 34
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patients with chronic recurrent VKH disease, about 76% achieved BCVA ≥20/40 (Abu El-Asrar et
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al., 2013). After one year treatment, 61 eyes (67.77%) of South Indian VKH patients (n=45; 90
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eyes, 23 patients presented in the acute phase) achieved BCVA of ≥ 20/40 (Murthy et al., 2007).
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Mondkar et al reported that only 15.4% of 87 consecutive Indian VKH cases (48 cases were seen
1278
within 3 months of onset of symptoms) retained a BCVA of 6/18 or better (Mondkar et al., 2000).
1279
A large cohort study including of 410 consecutive Chinese VKH patients showed that, with the
1280
treatment of corticosteroids alone or combined with other immunosuppressive agents, all the 73
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patients (146 eyes) referred to our clinical within 2 months after onset achieved a visual acuity of
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20/20 (Yang et al., 2007). For 337 patients (673 eyes) with recurrent ocular inflammation which
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were referred to our clinic 2 months after onset and were initially treated in other hospitals, up
1284
to 62.5% achieved a vision ≥20/40 (Yang et al., 2007). Most studies mentioned above show a
1285
good response to treatment suggesting that ethnicity or region does not affect the outcome. The
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only study mentioning a poor response might be due to problems concerning the access of
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appropriate medication (Mondkar et al., 2000).
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Initial visual acuity at presentation has been shown to be significantly associated with final visual acuity (Al-Kharashi et al., 2007; Ohno et al., 1988; Read et al., 2001a; Read et al., 2001b).
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Furthermore, recent studies showed that a good visual acuity at one month after starting
1291
treatment predicted a good prognosis (Chee et al., 2009). Prompt administration of
1292
corticosteroids and slowly tapering them off is critical for the good prognosis of acute VKH
1293
disease (Read et al., 2001b). However, more than half of these patients may develop chronic
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disease with consequent poor visual prognosis due to delayed treatment (later than 15 days from disease onset) and inadequate treatment (suboptimal dose and time of maintaining treatment)
(Chee et al., 2007; Kawaguchi et al., 2010; Lai et al., 2009), though different oral corticosteroid regimens have been explored. Cataract, glaucoma, subretinal fibrosis, choroidal
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neovascularization, or choroidal atrophy are the main complications associated with a poor
1299
prognosis (Chee et al., 2007; Kawaguchi et al., 2010; Lai et al., 2009; Yang et al., 2007). Patients
1300
treated initially with immunosuppressive agents had a better visual outcome than those who
1301
received a prolonged treatment with corticosteroids alone (Paredes et al., 2006). Other studies 44
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and our data also confirmed the benefit of first-line immunomodulatory therapy for improving
1303
visual acuity and controlling inflammation (Abu El-Asrar et al., 2013; Paredes et al., 2006; Urzua
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et al., 2015). In addition, triple-agent therapy, including corticosteroids, azathioprine, and
1305
cyclosporine, was associated with a rapid remission in a series of severe recalcitrant VKH cases
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(Agarwal et al., 2006).
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Literature reports concerning the role of age at disease onset and prognosis of visual
1308
acuity show conflicting data. Some studies showed a poor prognosis with older age at VKH onset
1309
(Chee et al., 2009; Read et al., 2001b) whereas others reported a worse prognosis in young
1310
patients (Ohno et al., 1988; Tabbara et al., 1998). The visual prognosis of child VKH disease seems
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to be quite variable depending on the time interval between onset of the disease and treatment
1312
(Abu El-Asrar et al., 2008; Rathinam et al., 1998; Tabbara et al., 1998). Pregnancy showed a
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beneficial effect on disease activity (Wang and Chan, 2014). Ocular inflammation usually
1314
improved during pregnancy and rebounded after delivery (Chiam et al., 2013; Friedman et al.,
1315
1980; Kump et al., 2006; Nohara et al., 1995; Rabiah and Vitale, 2003; Snyder and Tessler, 1980;
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Steahly, 1990), though in some cases disease did not recur after delivery (Friedman et al., 1980).
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Future directions
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VKH disease, a bilateral uveitis frequently associated with manifestations of the skin,
1319
auditory system and meninges, is common in certain ethnic populations with a susceptible
1320
genetic background. In addition to HLA antigens, several other genetic susceptibility factors have
1321
been identified and most of the factors identified so far are involved in the common pathways of
1322
autoimmune disease. Although various VKH disease specific predisposing genetic factors have
1323
been identified, it is expected that many more will be identified in the near future. .The exact role
1325 1326 1327
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of these predisposing factors and how their genetic basis causes the development of VKH disease needs further investigation. A complex network, including T cells, cytokines, chemokines, and transcription factors are
instrumental in keeping the balance between tolerance and autoimmunity against melanocyte
1328
associated antigens. Disturbance of this homeostatic balance is considered as the initial event in
1329
the pathogenesis of VKH disease. The steps leading to the disturbance of immune homeostasis
1330
are far from clear however. Environmental factors such as the microbiome are currently
1331
considered as possible precipitating factors in the development of ocular inflammatory disease. 45
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Novel techniques examining the composition of the microbiome in VKH patients may elucidate
1333
whether the microbial flora plays a role in the initiation or recurrence of this disease, how the
1334
microbiome interacts with predisposing genetic factors and its effects on autoimmunity and
1335
inflammation and whether this knowledge can be integrated in its treatment.
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The diagnosis of VKH disease is mostly based on clinical manifestations. Therefore, it is
1337
extremely important to be familiar with the evolutionary progress of the disease, because the
1338
clinical features at the different stages vary greatly. Further identification of biomarkers is needed
1339
to unravel disease mechanisms and to investigate whether they can be used to follow disease
1340
progress and its response to therapy.
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High-dose corticosteroids are still the mainstay of therapy for VKH disease. However, mounting evidence for the efficacy of immunosuppressive agents and biologic agents is being
1343
reported. Is it necessary to employ immunosuppressive agents and biologic agents as the first
1344
line therapy? How to determine the duration and dosage of immunosuppressive agents for
1345
patients? How to maximize the role of the newly developed ancillary tests for diagnosis,
1346
follow-up and evaluating the efficacy of therapies? Multi-centered, prospective, randomized
1347
studies are urgently needed.
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Acknowledgments
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This work was supported by Natural Science Foundation Project (81470620), Natural Science Foundation Major International (Regional) Joint Research Project (81320108009), Key
1351
Project of Natural Science Foundation (81130019), National Natural Science Foundation Project
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(31370893), Basic Research program of Chongqing (cstc2013jcyjC10001), Chongqing Key
1353
Laboratory of Ophthalmology (CSTC, 2008CA5003), National Key Clinical Specialties Construction
1355 1356 1357 1358
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1354
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Program of China, Key Project of Health Bureau of Chongqing (2012-1-003), Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002), National Natural Science Foundation Project of CQ (cstc2013jcyjA10015), and Fund for PAR-EU Scholars Program.
Competing financial interests The authors declare no competing financial interests.
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Figure legends
1360 1361
Fig 1. Schematic hypothesis for the pathogenesis of VKH disease: A, Two factors are involved in the initial stage of VKH disease, genetic factors and environmental triggers. Disease specific risk 46
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1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404
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factors such as HLA-DR4 and a number of other common “immune response” gene polymorphisms have been identified in VKH disease. These factors together determine the start of VKH disease. Virus is widely accepted as the triggering factor. However, permissive risk alleles and timing of triggering need further analysis. At the proper timing, dendritic cells and other innate immune cells meet pathogen-associated molecular pattern (PAMP) in the susceptible individuals. B, On the one hand, antigen presenting cells (APCs) become mature and present the PAMP to naïve T cells. Under the specific immune conditions of the individual, APCs secrete a certain profile of cytokines. This specific profile of cytokines determines the direction of differentiation of naïve T cells: Th1, Th17, Th2 or Tregs. In VKH disease, the overwhelming differentiation of T cells has been demonstrated to be shifted towards a population of Th1 and Th17 cells. C, Cytokines, chemokines and other factors secreted by Th1, Th17, Th2 and other types of immune competent cells constitute a specific immune environment in the susceptible individual. This immune environment in turn has an effect on the differentiation of naïve T cells directly or indirectly, forming a complicated network of immune response. D, The immune environment allows activation of effector T cells and other effector immune cells to attack tissue with pigment including the choroid, ear, skin and meninges. Selection of the target tissues in VKH disease may be due to the similarity between viral antigens and proteins from pigmented cells (molecular mimicry theory). Fig 2. Genes tested for susceptibility to VKH disease: The underlined bold genes have been shown to be associated with VKH disease.
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Fig 3. Fundus photography, autofluorescence and OCT examination of a patients with acute VKH disease. Multiple exudative retinal detachment (ERD), optic disc swelling and optic disk hyperemia were found in both eye.
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Fig 4. FFA and ICG of the same patient in Fig 3. Numbers of punctate hyperfluorescent dots are seen in the early stage of FFA. In the late phase of FFA, pooling of the dye in areas of an exudative retinal detachment, optic disc hyperfluorescence and leakage are noted. Early choroidal perfusion inhomogeneity and dot hyperfluorescence are noted in ICG. Fig 5. Schematic structure of biologic agents used in VKH disease
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Table 1 Criteria proposed by the American Uveitis Society for diagnosis of VKH diseasea 1) Patient should have no history of ocular trauma or surgery; 2) At least three of the following four signs should be present: a) bilateral chronic iridocyclitis;
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b) posterior uveitis, including exudative retinal detachment, formefruste of exudative retinal detachment, disk hyperemia or edema, and "sunset glow" fundus; c) neurologic signs of tinnitus, neck stiffness, cranial nerve or central nervous system problems, or CSF pleocytosis; d) cutaneous findings of alopecia, poliosis, or vitiligo. from Snyder and Tessler, 1980
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Table 2 Diagnostic criteria proposed by Sugiura for VKH disease (Sugiura, 1978) Major symptom 1. Acute bilateral uveitis with simultaneous involvement of both eyes. Symptoms may not be noted for 1–10 days in the second eye. Major symptom 2. Circumscribed retinal edema most markedly at the posterior pole. Fluorescein angiography reveals characteristic leakage of dye through the retinal pigment epithelium into the subretinal spaces.
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Major symptom 3. Pleocytosis of the cerebrospinal fluid is noted in the early stages of the disease. Dysacousia, vertigo, and scalp sensitivity when touching the hair are of value in early diagnosis, if present.
Minor symptom 1. Floating cells in the anterior chamber, granulomatous keratic precipitates, and iris nodules are important signs that may be absent in early stages.
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Minor symptom 2. Hair loss and depigmentation of the eye, skin, and hair are also important signs in the convalescent stage. Depigmentation of the corneal limbus (Sugiura’s sign) appears earliest(Friedman and Deutsch-Sokol, 1981), roughly 1 month after onset, and is also of value for confirming the early diagnosis if present.
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Table 3. Diagnostic Criteria for Vogt-Koyanagi-Harada Disease a Complete Vogt-Koyanagi-Harada disease (criteria 1 to 5 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis 2. No clinical or laboratory evidence suggestive of other ocular disease entities
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3. Bilateral ocular involvement (a or b must be met, depending on the stage of disease when the patient is examined) a. Early manifestations of disease
(1) There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disk hyperemia), which may manifest as one of the following (a) Focal areas of subretinal fluid, or (b) Bullous serous retinal detachments
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(2) With equivocal fundus findings; both of the following must be present as well:
(a) Focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence, pooling within subretinal fluid, and optic nerve staining (listed in order of sequential appearance) by fluorescein angiography, and b. Late manifestations of disease
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(b) Diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography. (1) History suggestive of prior presence of findings from 3a, and either both (2) and (3) below, or multiple signs from (3) (2) Ocular depigmentation (either of the following manifestations is sufficient): (a) Sunset glow fundus, or (b) Sugiura sign (3) Other ocular signs
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(a) Nummular chorioretinal depigmented scars, or (b) Retinal pigment epithelium clumping and/or migration, or (c) Recurrent or chronic anterior uveitis.
4. Neurological/auditory findings (may have resolved by time of examination).
b. Tinnitus, or
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a. Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors; headache alone is not sufficient to meet definition of meningismus, however), or
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c. Cerebrospinal fluid pleocytosis
5. Integumentary finding (not preceding onset of central nervous system or ocular disease) a. Alopecia, or b. Poliosis, or c. Vitiligo
Incomplete Vogt-Koyanagi-Harada disease (criteria 1 to 3 and either 4 or 5 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis, and 2. No clinical or laboratory evidence suggestive of other ocular disease entities, and 3. Bilateral ocular involvement. 4. Neurologic/auditory findings; as defined for complete Vogt-Koyanagi-Harada disease above, or 5. Integumentary findings; as defined for complete Vogt-Koyanagi-Harada disease above Probable Vogt-Koyanagi-Harada disease (isolated ocular disease; criteria 1 to 3 must be present)
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1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis. 2. No clinical or laboratory evidence suggestive of other ocular disease entities. 3. Bilateral ocular involvement as defined for complete Vogt-Koyanagi-Harada disease above. from Am J Ophthalmol2001:131, 647-652.
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Table 4
The ratio of pediatric VKH reported previously
Authors
Total VKH
Pediatric VKH (%)
Regions
97
13 (13.5%)
Riyadh, Saudi Arabia
(Rathinam et al., 1998)
98
3 (3.1%)
Madurai, India
(Martin et al., 2010)
267
22 (8.2%)
Madurai, India
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(Tabbara et al., 1998)
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Table 5
The proportion of male patients with VKH disease as reported previously Cases
Male (%)
Regions
(Ohno et al., 1977)
51
23(45.1%)
North California, USA
(Nussenblatt, 1988)
46
10(21.7%)
USA
(Snyder and Tessler, 1980)
20
8(40.0%)
USA
(Belfort Junior et al., 1988)
33
10 (30.3%)
Brazil
(Sasamoto et al., 1990)
47
29(61.7%)
Sapporo, Japan
(Rubsamen and Gass, 1991)
22
5(22.7%)
Miami, USA
(Beniz et al., 1991)
48
15(31.2%)
South California, USA
(Moorthy et al., 1995)
65
17(26.2%)
Los Angeles, USA
(Tabbara et al., 1998)
97
64(65.9%)
Riyadh, Saudi Arabia
(Kim et al., 2000)
18
7(38.9%)
South Korea
(Mondkar et al., 2000)
87
33(37.9%)
Chennai, India
(Yamaki et al., 2005)
49
19(38.8%)
Akita, Japan
(Chee et al., 2007)
89
37(42.13%)
Singapore
(Khairallah et al., 2007b)
49
17(34.7%)
Tunisia
45
(Yang et al., 2007)
410
(Horie et al., 2009)
167
(Yodmuang et al., 2012)
48
(Llorenc et al., 2015)
19
(Zheng et al., 2015)
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(Tugal-Tutkun et al., 2007)
18(37.5%)
South California, USA
13(34.6%)
Turkey
215(52.4%)
China
72(43.1%)
Sapporo or Yokohama, Japan
18(37.5%)
Thailand
3(15%)
Spain
134(67.3%)
China
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Table 6. The information on candidate genes which have been evaluated by different groups Genes
Functions
References
IL-23R
Interleukin-23 receptor, an important element for Th17 mediated responses
(Jiang et al., 2010)
IL-17
Interleukin-17, an important inflammatory factor identified recently
(Shu et al., 2010)
IFN-γ
Interferon gamma
(Horie et al., 2007)
IL-12B, IL-12Rβ1/β2
Interleukin-12 related subunit genes
(Li et al., 2014)
CTLA-4
Cytotoxic T lymphocyte-associated antigen-4, a critical negative regulator of the T cell-mediated immune response
(Du et al., 2008)
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Cytokines and their receptors
Transcription factors and related proteins
Small ubiquitin-like modifier 4, an transcription factor involved in the regulation of NF-кB
(Hou et al., 2008)
PTPN22
Protein tyrosine phosphatase non-receptor 22 gene, an important negative regulator of T cell activation
(Horie et al., 2009; Zhang et al., 2014)
Fc receptor-like 3 gene, an immunoregulatory gene
(Li et al., 2009)
leucine-rich repeat protein 1, a key regulator of the innate immune system
(Horie et al., 2011)
TGFBR3
Type III Transforming growth factor-β, a key factor in regulating and mediating transduction of TGF-β signaling
(Chen et al., 2012b)
Ets-1
Transcription factor Ets-1
(Zhou et al., 2012)
TNFAIP3
Encoding A20 protein, a negative regulator of the NF-KB signaling pathway
(Li et al., 2013)
FGFR10P
A gene region shown to be associated with a variety of
(Yi et al., 2013)
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autoimmune GWAS
diseases
by
A signaling target of a multitude of cytokines in autoimmune diseases
(Hu et al., 2013)
Bach2
A transcriptional repressor of Blimp-1 and member of the CNC family
(Gao et al., 2015)
TRAF5 and TRAF3IP2
Members from -receptor-associated family
TNF factors
(Xiang et al., 2014)
TNIP1
TNFa-induced protein 3 interacting with protein 1, an important regulator of NF-kB activity
(Kanda et al., 2014)
STAT4
Signal transducers and activators of transcription 4, a transcript involved in T cell differentiation and T cell-mediated response
(Hu et al., 2010)
Programmed cell death 1, an immunoinhibitory receptor inhibiting lymphocyte activation
(Meng et al., 2009)
Osteopontin, a proinflammatory cytokine involved in chronic inflammatory diseases
(Chu et al., 2011)
Toll-like receptor 9, a key receptor for recognizing pathogen-associated molecular patterns from viruses
(Ito et al., 2011)
A member of receptor family
(Chen et al., 2012a)
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PDCD1
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TLR9
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JAK1
CD40
the
TNF
microRNA and others miR-146a
MicroRNA-146a
(Zhou et al., 2012)
miR-182
MicroRNA-182, targeting the 3’ UTR of FoxO1 resulting in a decrease in Treg cells and subsequent clonal expansion of helper T cells
(Yu et al., 2014)
DHCR7, CYP2R1, CYP27B1,
Vitamin D family genes
(Fang et al., 2014)
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and CYP24A1 A susceptible locus for a large number of autoimmune diseases
(Li et al., 2015)
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CLEC16A
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Table 7.Studies on the efficacy of Infliximab on VKH disease reported previously Efficacy
2
Effective
(Khalifa et al., 2010)
2 children
Effective for one case
(Kahn et al., 2006)
2
Effective
(Niccoli et al., 2009)
2
Effective
(Suhler et al., 2009)
2
(Zmuda et al., 2013)
2
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Number (Chen et al., 2008)
helpful for one case
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S1350-9462(16)30003-9
DOI:
10.1016/j.preteyeres.2016.02.002
Reference:
JPRR 619
To appear in:
Progress in Retinal and Eye Research
Received Date: 11 December 2015 Revised Date:
7 February 2016
Accepted Date: 8 February 2016
Please cite this article as: Du, L., Kijlstra, A., Yang, P., Vogt-Koyanagi-Harada disease: Novel insights into pathophysiology, diagnosis and treatment, Progress in Retinal and Eye Research (2016), doi: 10.1016/j.preteyeres.2016.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment Liping Du1, Aize Kijlstra2,3, Peizeng Yang1
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1 The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China 2 University Eye Clinic Maastricht, Maastricht, Limburg, The Netherlands 3 Wageningen UR Livestock Research, Wageningen, The Netherlands * Correspondence to: Peizeng Yang, MD, PhD. Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, Chongqing, China. Tel: 86-023-89012851 Fax: 86-023-89012851 Email: [email protected]
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Abstract
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Vogt-Koyanagi-Harada (VKH) disease is one of the major vision-threatening diseases in certain
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populations, such as Asians, native Americans, Hispanics and Middle Easterners. It is
21
characterized by bilateral uveitis that is frequently associated with neurological (meningeal),
22
auditory, and integumentary manifestations. Although the etiology and pathogenesis of VKH
23
disease need to be further elucidated, it is widely accepted that the clinical manifestations are
24
caused by an autoimmune response directed against melanin associated antigens in the target
25
organs, i.e. the eye, inner ear, meninges and skin. In the past decades, accumulating evidence has
26
shown that genetic factors, including VKH disease specific risk factors (HLA-DR4) and general risk
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factors for immune mediated diseases (IL-23R), dysfunction of immune responses, including the
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innate and adaptive immune system and environmental triggering factors are all involved in the
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development of VKH disease. Clinically, the criteria of diagnosis for VKH disease have been further improved by the employment of novel imaging techniques for the eye. For the treatment,
early and adequate corticosteroids are still the mainstream regime for the disease. However,
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immunosuppressive and biological agents have shown benefit for the treatment of VKH disease,
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especially for those patients not responding to corticosteroids.
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This review is focused on our current knowledge of VKH disease, especially for the diagnosis,
35
pathogenesis (genetic factors and immune mechanisms), ancillary tests and treatment. A better 1
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understanding of the role of microbiome composition, genetic basis and ongoing immune
37
processes along with the development of novel biomarkers and objective quantitative assays to
38
monitor intraocular inflammation are needed to improve current management of VKH patients.
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Keywords: Vogt-Koyanagi-Harada disease; Genetic background; immune mechanisms; clinical
40
features; therapy
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Contents
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Abstract ..................................................................................................................................... 1
43
Introduction ............................................................................................................................... 3
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History ....................................................................................................................................... 4
45
Diagnostic criteria ...................................................................................................................... 5
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Epidemiology ............................................................................................................................. 8
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Etiology and pathogenesis....................................................................................................... 11
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Genetics ............................................................................................................................... 12
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HLA-antigens.................................................................................................................... 12
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Killer immunoglobulin-like receptors .............................................................................. 14
51
Immunogenetics and VKH disease .................................................................................. 16
52
Pathology ............................................................................................................................. 19
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Immunopathology ............................................................................................................... 20
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Antigens ........................................................................................................................... 21
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Immune responses .......................................................................................................... 22
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Triggering factors ............................................................................................................. 27
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Clinical features ....................................................................................................................... 28 Stage of VKH disease ........................................................................................................... 29 Prodromal stage .............................................................................................................. 29 Acute stage ...................................................................................................................... 29
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Chronic (convalescent) stage........................................................................................... 30
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Chronic recurrent stage ................................................................................................... 31
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Staging system in the Chinese population ...................................................................... 32
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Complications ...................................................................................................................... 32 2
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Ancillary tests ...................................................................................................................... 34
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Fluorescein angiography (FA) .......................................................................................... 34
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Ultrasonography .............................................................................................................. 34
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Lumbar puncture ............................................................................................................. 34
69
Indocyanine green angiography (ICGA) ........................................................................... 35
70
Optical coherence tomography (OCT) ............................................................................. 35
71
Other ancillary tests ........................................................................................................ 36
72
Therapy .................................................................................................................................... 37
73
Corticosteroids .................................................................................................................... 37
74
Immunosuppressive agents................................................................................................. 39
75
Biologic agents..................................................................................................................... 40
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Management of VKH in special groups ............................................................................... 42
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Management of complications............................................................................................ 42
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Prognosis ................................................................................................................................. 43
79
Future directions ..................................................................................................................... 45
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Acknowledgments ................................................................................................................... 46
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Competing financial interests.................................................................................................. 46
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Figure legends ......................................................................................................................... 46
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References ............................................................................................................................... 47
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Introduction
Vogt-Koyanagi-Harada (VKH) disease is an immune-mediated disorder characterized by
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bilateral uveitis frequently associated with neurological (meningeal), auditory, and integumentary manifestations.
The uveitis characteristic of VKH disease is generally divided into four stages or an
evolutionary four-step process: prodromal stage, acute uveitis stage, chronic convalescent stage
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and chronic recurrent stage (Moorthy et al., 1995; Read et al., 2001a). Neurological
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manifestations (including headache, neck and back stiffness, abnormal sensitivity to touch of the
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hair) and auditory manifestations (tinnitus, hearing loss and vertigo) usually occur before or
95
concurrently with ocular involvement, whereas integumentary manifestations (including alopecia, 3
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poliosis and vitiligo) always arise after the uveitis attack (Fang and Yang, 2008; Moorthy et al.,
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1995; Read et al., 2001a).
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Although the etiology and pathogenesis of VKH disease is not completely known, a great number of studies in the past decades have shed more light on this issue. In individuals with a
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predisposing genetic background (HLA-DR4), certain environmental factors (for instance viral
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infection) trigger the immune response, especially the adaptive immune response. This leads to a
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Th1 and Th17 cell activation directed against self-antigens (for instance tyrosinase) expressed by
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melanocytes in various organs resulting in a multisystemic acute autoimmune disease.
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Although glucocorticosteroids and immunosuppressive agents are still the most often prescribed drugs for VKH disease, biologic anti-inflammatory (anti-TNF-α antibody) and
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anti-neovascular (anti-VEGF) therapy that have been introduced in the past two decades, offer
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promising modalities to patients with sight-threatening recurrent inflammation or severe
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neovascularization (Busanyova et al., 2013; Wu et al., 2009).
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With the rapid progress in immunology, genetics and technology, great progress has been made in both basic and clinical research of VKH disease. The present article aims to review the
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latest studies on the immune and genetic pathogenesis of VKH, the new techniques for diagnosis
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and follow-up, the latest treatment regime, as well as the definition, epidemiology, clinical
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features, and the gradual progress in criteria for diagnosis of VKH disease.
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History
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Vogt-Koyanagi-Harada disease was first described in a report on the association of
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nontraumatic idiopathic uveitis with poliosis by Vogt (Vogt, 1906). In this report, Vogt considered
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this condition as a new entity of unknown disease. Cases reported subsequently and the
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landmark reviews by Koyanagi (Koyanagi, 1929) in 1929 drew more attention of ophthalmologists
to the disease. A syndrome, bilateral non-traumatic uveitis with poliosis, vitiligo, alopecia and
dysacousia, was integrated from sixteen cases (10 from literature and 6 from his observation)
described in Koyanagi’s review (Koyanagi, 1929). Based on this extensive review and the
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uniformity among these cases, most authors agree that cases reported by Vogt and Koyanagi
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were indeed one disease entity and accepted the name Vogt-Koyanagi syndrome for this
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condition. On the other hand, the road for integration of Harada’s disease into Vogt-Koyanagi
125
syndrome was not so smooth, even though Harada’s disease and Vogt-Koyanagi syndrome were 4
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considered as one condition early in 1932 by Babel (Babel, 1932). Harada’s disease was first
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described as a separate uveitis entity in 1926 (Harada, 1926)and was characterized by a
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complicated retinal detachment and pleocytosis in the cerebrospinal fluid (CSF). Subsequently,
129
based on reports by Parker (Parker, 1940), Rados (Rados, 1940, 1941) and some others in the
130
Japanese literature, earlier researchers were inclined to differentiate the Vogt-Koyanagi
131
syndrome from Harada’s disease by the high rate of retinal detachment and alopecia with poliosis
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and lower rate of anterior uveal involvement in the latter. With the increasing numbers of reports
133
for the intermediate form of bilateral uveitis with mixing features for two conditions, more and
134
more researchers considered the two separate conditions as different clinical variations in a same
135
underlying process (Bruno and McPherson, 1949; Cowper, 1951a). Recently, based on a study of
136
410 Chinese VKH patients, we came to the conclusion that both conditions represent the clinical
137
manifestations of an evolutionary disease process instead of being two separate disease entities
138
(Yang et al., 2007). At the onset, the disease always shows a diffuse choroiditis frequently in
139
association with exudative retinal detachment. The disease eventually progresses to a recurrent
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granulomatous anterior uveitis if no appropriate treatment is given.
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“Uveomeningoencephalitic Syndrome”, “Uveomeningoencephalitides” or
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“Uveomeningoencephalitis” (Cowper, 1951b; Vancea and Lazarescu, 1958). However,
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Vogt-Koyanagi-Harada disease/syndrome is now the most widely accepted term.
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Diagnostic criteria
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Several sets of criteria have been proposed for the diagnosis of VKH disease, since it was
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initially considered as a single clinical uveitis entity. The evolution of the criteria represents the
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process of our gradual understanding of the disease. Based on the observation of a bilateral
acute diffuse uveitis together with various typical extraocular features, the diagnosis of VKH
disease is not difficult, although there may be a great similarity between this disease and
sympathetic ophthalmia, which is also characterized by an acute bilateral uveitis with alopecia,
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vitiligo, poliosis and deafness. The latter however usually takes place after ocular trauma or
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intraocular surgery and rarely presents with extraocular manifestations. A consensus for
154
diagnostic criteria of VKH disease was reached at the second annual meeting of the American
155
Uveitis Society (AUS), in Kansas City, Missouri in 1978 (Snyder and Tessler, 1980) (Table 1). 5
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The AUS criteria were widely used in a series of studies since their appearance. Although the acceptance of AUS criteria facilitated the communication between different investigators,
158
these criteria do not embody the different manifestations observed during disease progression.
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Two of the four criteria, namely b) and d), are features that are only observed in the late course
160
of the disease. Using these criteria, it is therefore not easy to make a correct diagnosis of an early
161
stage of VKH disease. These criteria were therefore not suitable for planning prospective studies
162
of VKH disease (Read et al., 2001a). In addition, the AUS criteria did not include the evaluation by
163
ultrasonography and fluorescein angiography, which has been shown to be of great help in the
164
diagnosis of VKH disease (Forster et al., 1990).
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About the same time that the AUS criteria were published, a set of criteria were also
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proposed by Sugiura (Sugiura, 1976a, 1978). These latter criteria paid more attention to the
167
manifestations observed during the early stages of disease. These features include acute bilateral
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uveitis, circumscribed retinal edema, pleocytosis of the CSF, depigmentation of the corneal
169
limbus, dysacousia, vertigo and supersensitivity of the skin on touching the hair. Sugiura’s criteria
170
thus seemed more suitable for the diagnosis of early VKH disease. However, Sugiura’s criteria
171
were seldom accepted outside Japan for two reasons: depigmentation of the corneal limbus
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(Sugiura’s sign) is not often observed in patients with VKH disease outside Japan and due to the
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fact that these criteria include CSF analysis, which is an invasive test that is not performed in a
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department of Ophthalmology.
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the accuracy/sensitivity of the AUS criteria for the diagnosis of VKH disease. In that study, 71
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consecutive patients with VKH disease were evaluated according to the AUS diagnostic criteria
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with manifestations present at the initial presentation. The results showed that patients presenting in the acute, subacute and chronic stages met the AUS criteria for VKH disease in 56%,
48% and 58% of cases, respectively (Read and Rao, 2000). This study showed that the AUS criteria
were not adequate for the evaluation of patients with VKH disease. Therefore, more precise
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diagnostic criteria with increased sensitivity and specificity were needed for both the clinical
183
ophthalmologist and basic science investigators. Revised Diagnostic Criteria (RDC) for VKH
184
disease were proposed at the First International Workshop on Vogt-Koyanagi-Harada Disease on
185
October 19-21, 1999 in California (Read et al., 2001a) (Table 3). 6
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The revised criteria have the advantage that they include the difference in clinical manifestations of VKH disease at varying stages of the disease and that it uses the results of
188
ancillary examinations (fluorescein angiography and ultrasonography). The ocular manifestations
189
are more comprehensively delineated according to the early and late stages of the disease. The
190
RDC includes five sections: the exclusion criteria for sympathetic ophthalmia, the exclusion of
191
other uveitis entities (sarcoidosis, syphilitic uveitis, tuberculous uveitis, Lyme disease, posterior
192
scleritis, intraocular lymphoma, central serous choroidopathy, uveal effusion syndrome), the
193
ocular manifestations of the early and late stages, the neurological/auditory findings and the
194
integumentary findings. It divides VKH disease into three categories, “complete”, “incomplete”
195
and “probable” (Table 3). For the complete type, bilateral ocular involvement,
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neurological/auditory findings and integumentary abnormalities must be present, while the
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incomplete type has either neurological/auditory or integumentary symptoms. The probable type
198
has only ocular manifestations. The first two categories are considered as a certain diagnosis. The
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probable VKH disease category, also referred to as “ocular VKH disease”, needs a continued
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surveillance for signs that would confirm or refute the definite diagnosis of VKH disease (Read et
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al., 2001a).
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Since the appearance of the RDC in 2001, various comparisons with the Sugiura criteria were published (Cardoso et al., 2008; da Silva et al., 2009a; Kitamura et al., 2005; Rao et al., 2007;
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Yamaki et al., 2005) in different ethnic groups. Yamaki et al. (Yamaki et al., 2005) studied 49
205
patients with VKH disease diagnosed at the Akita University School of Medicine Hospital and
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re-classified them into complete and incomplete VKH disease according to the RDC. In their
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assessment the RDC was not as effective as Sugiura’s criteria for establishing the diagnosis at the
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early stages of VKH disease (Yamaki et al., 2005). This is not surprising since 40.9% of their VKH patients only had ocular manifestations (Rao et al., 2007). If the probable VKH disease was
considered as a category of VKH disease in that study, the RDC would have been as sensitive as Sugiura’s criteria. The RDC were also compared to the Sugiura’s criteria by Kitamura et al.
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(Kitamura et al., 2005) and to the AUS criteria by da Silva et al. (da Silva et al., 2009a) and to both
213
criteria by Rao et al. (Rao et al., 2007). These studies all showed that the RDC is highly sensitive
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and specific for the diagnosis of VKH disease both at the early and late stages. Our own studies
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showed that the RDC is very useful for the diagnosis of Chinese VKH patients (Yang et al., 2007). 7
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In our uveitis clinic, we observed that some patients presenting with a sunset glow fundus and
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Dalen-Fuchs nodules had a typical evolutionary process of uveitis and lacked extraocular
218
manifestations before the onset of uveitis and during the whole follow-up time. We classified
219
these patients, which should be considered as probable VKH disease according to the RDC, as
220
ocular VKH disease (Yang, 2004). A recent prospective international study performed by Rao et al.
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(Rao et al., 2010) showed that VKH disease can present in patients with clinical findings limited to
222
the eye without extraocular findings in the form of bilateral uveitis associated with exudative
223
retinal detachment at the early stage or in the form of sunset glow fundus at the late stage. This
224
study reinforced the importance of the diagnosis of the probable VKH disease category in the
225
RDC classification. Based on these features, we would like to argue that the probable VKH disease
226
category should be considered as a genuine ocular VKH disease characterized by a lack of
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extraocular manifestations.
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Epidemiology
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Although population-based epidemiological studies about VKH disease are relatively rare, epidemiological data based on studies from tertiary referral centers have shown that the
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incidence of VKH disease varies greatly worldwide. VKH disease is one of the most common
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diseases causing panuveitis in North Asia, accounting for 7%-10% of all uveitis referrals (Kotake et
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al., 1997; Ohguro et al., 2012; Sugita et al., 1993; Wakabayashi et al., 2003) in Japan and
234
11%-22.4% in Thailand (Pathanapitoon et al., 2008; Silpa-Archa et al., 2014). Results from 1752
235
uveitis patients referred to our uveitis clinic showed that VKH disease was the second most
236
common entity causing panuveitis, accounting for 15.9% of all uveitis cases in China (Yang et al.,
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2005). The incidence of VKH disease is also high in the Middle East. It was reported to be
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19.4%-19.6% of all uveitis cases in Saudi Arabia (Al-Mezaine et al., 2010; Al Dhahri et al., 2014)
and 12.3% in Iraq (Al-Shakarchi, 2014). This was much higher than the 3.9% of all 544 uveitis
cases reported in Iran by Soheilian et al (Soheilian et al., 2004). A study from Tunesia showed that
4.4% of 472 uveitis cases had VKH disease (Khairallah et al., 2007a). According to Couto and
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Merlo (Couto and Merlo, 1993), VKH disease is also common in South America and it was the
243
most common cause of panuveitis accounting for 13.3% of all uveitis referrals in Argentina and
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17.2% in Chile (Liberman et al., 2014). VKH accounts for 1.2%-2.2% of uveitis case encountered in
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India (Martin et al., 2010; Mondkar et al., 2000). In contrast to the high prevalence of VKH 8
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disease in the populations described above, it is relatively less frequent in European populations
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such as England (＜1%) (Perkins and Folk, 1984), the Netherlands (＜1%) (Rothova et al., 1992;
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Smit et al., 1993), Finland (none mentioned) (Paivonsalo-Hietanen et al., 2000;
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Paivonsalo-Hietanen et al., 1994),Turkey (1%) (Sengun et al., 2005; Tugal-Tutkun et al., 2007),
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Austria (0.4%) (Barisani-Asenbauer et al., 2012), and Italy (1.4%-2.1%) (Cimino et al., 2010;
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Mercanti et al., 2001; Pivetti-Pezzi et al., 1996b). It accounts for 1%-4% of all uveitis referrals in
252
the United States (Ohno et al., 1977; Snyder and Tessler, 1980). The relative higher incidence of
253
VKH disease when compared with that in European populations may be due to the multiple
254
ethnic populations residing in the USA (Beniz et al., 1991; Nussenblatt, 1988). Some investigators
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reported that 54%-78% of VKH patients in the US had a Hispanic background (Moorthy et al.,
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1995; Rubsamen and Gass, 1991), whereas others claimed that Asian and American Indians
257
comprised the majority of VKH patients in this country (Nussenblatt, 1988; Ohno et al., 1977).
258
The presence of many individuals with a Hispanic or Asian background may contribute to the
259
incidence of VKH disease in the United States. Therefore, based on these epidemiological studies
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from tertiary referral centers, it is now widely accepted that VKH disease affects certain heavily
261
pigmented populations (Asians, Hispanics, American Indians, and middle Easterners) and is rarely
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seen in Caucasians in Europe and Black people in Africa (Rao et al., 1995; Read et al., 2001a;
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Sugiura, 1978). If pigmentation would be the major risk factor for VKH disease, then one would
264
expect a high incidence in the Black population in Africa. They are rarely affected by VKH disease,
265
which indicates that there might be differences in the pigmentation pathways in blacks as
266
compared to other heavy pigmented populations in the world. If ethnicity would be a critical risk
267
factor for VKH disease, one would expect that populations from the same ethnic background
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would have a similar incidence. As a matter of fact, the incidence of VKH disease varies greatly in
subpopulations of the same ethnicity. There is for instance a great difference in the incidence of
VKH disease between an Arab population from Saudi Arabia (Al-Mezaine et al., 2010) as
compared to an Arab population from Iran or Tunisia (Khairallah et al., 2007a; Soheilian et al.,
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2004). This would argue in favor of a role for an environmental factor between these countries
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since the genetic background of the population is expected to be very similar. The very low
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prevalence of disease in a neighboring country such as Turkey is also unexpected although the
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ethnic majority of this population does not consist of Arabs but is made up of Turks (Sengun et al., 9
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2005; Tugal-Tutkun et al., 2007). Also, the incidence (2%) of VKH disease reported in Korea
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(Chung and Choi, 1989) was much lower than that in other East Asian populations, such as in
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Japan, China and Thailand (Kotake et al., 1997; Sugita et al., 1993; Wakabayashi et al., 2003; Yang
279
et al., 2007). In addition, a Hispanic background was reported to represent the majority of
280
patients with VKH disease in the United States (Moorthy et al., 1995; Rubsamen and Gass, 1991).
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However, in an urban multi-ethnic population from Barcelona (Spain), 19 patients with VKH
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disease only accounted for about 1% of all 1022 patients with uveitis (Llorenc et al., 2015). Of
283
these 19 patients, 9 patients were born in South America (Llorenc et al., 2015). Genetic
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susceptibility plays an important role in the development of VKH disease and it is possible that
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with the global migration of ethnic populations, selection has taken place thereby changing the
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genetic predisposition to VKH. On the other hand environmental factors such as certain microbial
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infections may also play a role and the exposure of similar ethnic populations to other
288
environmental circumstances may explain differences in the prevalence of an autoimmune
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disease such as VKH.
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VKH disease predominantly affects people in their second to fifth decade of life (Moorthy et al., 1995; Yang et al., 2007), though children as young as 3 years (Al Hemidan et al., 2006;
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Takada et al., 2015) and elderly patients as old as 89 years have also been reported (Yamamoto et
293
al., 2007). Although a number of pediatric patients with VKH disease were reported, including
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several studies from tertiary centers (Table 4), VKH disease in children is relatively uncommon
295
(Martin et al., 2010). Pediatric patients (age ≤16 years) with VKH disease accounted for 3.1% to
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13.4% of all patients with VKH disease (Table 4) (Martin et al., 2010; Rathinam et al., 1998;
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Tabbara et al., 1998). In addition, based on information of 128 pediatric patients with VKH
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disease, girls were more likely to be affected (Martin et al., 2010). As for elderly patients with
VKH disease, one study suggested that the ratio of elderly VKH patients has increased yearly. Of the 68 patients with VKH disease reported by Kiyomoto et al (Kiyomoto et al., 2007), seven (10%)
were classified as elderly (age ≥65 years) at onset.
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Gender plays a role in the occurrence of VKH disease (Wang and Chan, 2014). Most studies
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revealed that 55%-78.3% of VKH patients were female (Table 5). In our own studies in 410
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Chinese patients we did not find a gender effect (Yang et al., 2007). In Japan, a varying gender
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ratio has been reported by different investigators. Although Sugiura (Sugiura, 1978) did not 10
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observe a gender effect, other investigators found that males were less likely to be affected than
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females (Horie et al., 2009; Yamaki et al., 2005). On the other hand, Sasamoto et al. (Sasamoto et
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al., 1990) reported that 29 (61.7%) of their 47 patients with VKH disease were male. A recent
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prospective study performed by 10 uveitis centers showed that 75% of patients with acute uveitis
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caused by VKH disease were female, while the female frequency was 68.1% in patients with
311
chronic uveitis caused by this disease (Rao et al., 2010). It thus appears that females are more
312
likely to develop VKH disease, although the differences in sexual dimorphism are small (table 5).
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A possible explanation for gender differences found in VKH include a role for sex hormones,
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including estrogen and progesterone, that are believed to account for gender differences in the
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prevalence of autoimmune disorders in general (Wang and Chan, 2014).
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Etiology and pathogenesis
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Although the precise etiology and pathogenesis of VKH disease remains to be elucidated,
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great progress has been made during past decades with the rapid development in various fields
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of basic science. Viruses discovered in patients with VKH disease reinforce the triggering role of a
320
microbial infection in the disease. Meningeal manifestations, such as fever, headache and
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meningismus in the prodromal stage have led to the hypothesis that a viral infection might
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provoke VKH disease. The group of Mochizuki has provided evidence for a role of
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cytomegalovirus in this disease (Sugita et al., 2007; Sugita et al., 2006), although earlier studies
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suggested herpes viruses were not involved (Hotta et al., 1996). The strong association with
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HLA-class II alleles and Th1 and Th17 cells would not be in favor of a viral pathogenesis since then
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one would expect a link with HLA-class I and CD8 cells. On the other hand, a viral infection may
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indirectly cause VKH disease as a triggering factor, whereby a disease association with HLA-class I
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alleles is not necessary. In this hypothesis, certain viral antigens may mimic self-proteins which
can be recognized by specific HLA-class II molecules (molecular mimicry), subsequently triggering
the inflammatory autoimmune response. Further research is needed to substantiate the viral hypothesis to be sure that it is not a spurious link. Monozygotic twins affected by VKH disease and the strong association with the human
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leukocyte antigens DR4 and DRw53 (HLA-DR4 and HLA-DRw53) indicates that it may occur in
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individuals with a susceptible genetic background. The discovery of uveal antigens, such as
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S-antigen, interphotoreceptor retinoid binding protein (IRBP) (Chan et al., 1985) and tyrosinase 11
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(or tyrosinase-related proteins) (Sugita et al., 1996) lays a foundation for the autoimmune nature
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of this disease. Immune cells located within choroidal inflammatory foci, T helper (Th) cells
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(including Th1 and Th17) and cytokines involved in this diseases emphasize the critical role of the
339
immune response in its pathogenesis (Andreoli and Foster, 2006; Chi et al., 2007; Imai et al., 2001;
340
Li et al., 2005; Miyazawa et al., 2005; Norose and Yano, 1996). Currently, evidence accumulated in
341
the past decades suggests that VKH disease occurs in individuals with a predisposing genetic
342
background. The disease is triggered by as yet unknown factors leading to an immune response
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directed against certain autoantigens (Fig 1). We will provide further details concerning this
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statement in the following sections.
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Genetics
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HLA-antigens
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First of all, VKH disease is not a genetic disease complying with Mendelian inheritance and it usually occurs sporadically. The genetic role in the pathogenesis of the disease is intuitively
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recognized by the high incidence of the disease in populations with heavier pigmentation and the
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coincidence in siblings (Benedict and Benedict, 1951) or monozygotic twins (Ashkenazi et al.,
351
1991; Ishikawa et al., 1994; Itho et al., 1992). A genetic predisposition became apparent when a
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strong association was found with certain HLA antigens (Supplementary Table 1). The HLA
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antigens first reported to be associated with VKH disease in Japan were HLA-BW22J and LD-Wa
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(Tagawa et al., 1976; Yakura et al., 1976), although Ohno et al (Ohno et al., 1976) were not able to
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replicate the association in 9 VKH patients in California. The discrepancy between these two
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studies might be due to a different genetic background in different ethnic populations or the
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small sample size. These first studies were soon overshadowed by the strong association in
Japanese patients with two other HLA antigens, namely HLA-DR4 and HLA-DRw53 (Ohno, 1981).
The confirmation of this association in other ethnic populations was first reported in Chinese Han.
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Twenty-five Chinese Han patients with VKH disease and 65 healthy controls were genotyped for
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HLA-A, B and DR alleles by Zhao et al (Zhao et al., 1991) and results showed that HLA-DRw53
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(positive in all 25 patients) and HLA-DR4 (positive in 20 patients) was indeed closely associated
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with VKH disease with a relative risk of 16.0 and 34.2, respectively (Zhao et al., 1991). 12
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Subsequently, this association was replicated in different ethnic populations, such as American
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(Davis et al., 1990), Hispanic (Weisz et al., 1995), Vietnamese (Riddington et al., 1996), Italian
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(Pivetti-Pezzi et al., 1996a), Brazilian (Goldberg et al., 1998), Mexican (Arellanes-Garcia et al.,
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1998) and Korean (Kim et al., 2000) patients, though some novel VKH disease associated HLA
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antigens, such as HLA-DQw3, were also identified in certain populations. Furthermore, other
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HLA-antigens, such as HLA-B54, HLA-DQ4 and HLA-DR1 (sharing a common epitope with HLA-DR4
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encoded by the HLA-DRβ-1 gene), were also shown to be associated with VKH disease, although
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the associations appeared to be population dependent (Islam et al., 1994; Shindo et al., 1994;
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Weisz et al., 1995). With the development of newer methods for HLA genotyping, HLA antigens in
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patients with VKH disease were subsequently mapped at the genomic level. In two independent
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original studies, HLA-DRB1*0405, HLA-DQA1*0301 and HLA-DQB1*0401 alleles have been shown
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to predominate in Japan (Islam et al., 1994; Shindo et al., 1994), although Islam et al (Islam et al.,
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1994) identified DQA1*0301, while Shindo et al (Shindo et al., 1994) concluded that two other
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alleles (HLA-DRB1*0405 and HLA-DQB1*0401) were the primary susceptibility factor for VKH
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disease. The strong association of HLA-DRB1*0405 and HLA-DQB1*0401 with VKH disease was
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confirmed in China (Min et al., 2007; Xiao et al., 1997; Zhang et al., 2000), Brazil (Goldberg et al.,
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1998), Korea (Kim et al., 2000) and Saudi Arabia (Iqniebi et al., 2009). It could not be confirmed
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for Hispanics in Southern California and Mexican mestizo (Alaez et al., 1999; Arellanes-Garcia et
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al., 1998; Levinson et al., 2004; Weisz et al., 1995). Hispanic and mestizo patients in fact showed a
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weak association with HLA-DR1 and DR4. As for the HLA alleles, these patients showed an
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association with HLA-DRB1*0404/*0407/*0410 and HLA-DQA1*03011/80302 (Arellanes-Garcia
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et al., 1998; Levinson et al., 2004). Alaez et al. (Alaez et al., 2011) found that HLA-DRB1∗04:05,
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HLA-DRB1∗04:04, and HLA-DQB1∗03:02 HLA alleles were restricted only to female VKH patients,
implying an association of HLA antigens with female predilection in VKH. Recently, we performed
a genome-wide association study to explore the genetic background for VKH disease. Our study
confirmed the strong association of the HLA gene region with VKH disease and several VKH
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disease associated SNPs were identified (Hou et al., 2014a). However, because of the complexity
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of these region, the relation of these VKH associated SNPs should further be assessed by fine
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DNA sequencing. Which of the VKH-disease-associated HLA class II antigens, is most important in
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conferring susceptibilitiy to VKH disease remains to be solved. It appears that multiple 13
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HLA-antigens or alleles can confer risk for VKH disease depending on the ethnic population. A
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systematic review and meta-analysis for 1853 VKH patients and 4164 controls from 21 articles
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showed that the strength of association depends on the ethnic group investigated (Shi et al.,
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2014). HLA-DRB1*0404, 0405 and 0410 are risk sub-alleles for VKH disease, while 0401 is a
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protective sub-allele (Shi et al., 2014).
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HLA-DRB1 is expressed on the cell surface and acts as a receptor, that binds a specific
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peptide, and depending on the genetically determined configuration of its antigen binding groove,
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can present this to cells of the immune system. If cells of the immune system contain a matching
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receptor for the HLA-DRB1-peptide complex it will result in an expansion of these cells finally
403
leading to an attack of tissues expressing these peptides. As mentioned earlier, VKH patients are
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sensitized to melanocyte antigens and an explanation concerning a possible association of certain
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genetic HLA-DRB1 variants with the disease is sought in differences in their melanocyte peptide
406
binding capacity. In this context it has been proposed that the risk HLA-DRB1*0405 may
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recognize a broad melanocyte-antigen peptide repertoire, whereas the protective
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HLA-DRB1*0401 may have a limited binding capacity for melanocyte associated antigens (Damico
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et al., 2005a; Shi et al., 2014).
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Of interest is the observation that an association has only been observed with HLA class II antigens and not with class I antigens. HLA class II is thought to be involved in the presentation of
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extracellular antigens to T cells, whereas HLA class I molecules present intracellular antigens.
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Different HLA antigens or alleles, which may precipitate the onset of the disease or determine the
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clinical course of the disease in different populations, could present the same immunogenic
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peptides to immune cells. Although a number of studies predicting HLA binding of antigens in
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silico and studies examing common peptides for different HLA-antigens were performed
(Hennecke and Wiley, 2002; Prasad and Levinson, 2005; Shindo et al., 1994; Sugita et al., 2006),
further studies are needed to provide additional insight into the possible mechanisms explaining the association between certain HLA antigens and VKH disease. Killer immunoglobulin-like receptors Killer immunoglobulin-like receptors (KIR), clustering on Chromosome 19q13.4, can either activate or inhibit natural killer cells and certain subsets of T lymphocytes (Lanier, 2005; Vilches 14
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and Parham, 2002). KIRs are generally divided into inhibitory KIRs (2DL1, 2, 3, 5 and 3DL1, 2, 3)
424
and activating KIRs (2DS1, 2, 3, 4, 5 and 3DS1). HLA class I genes serve as the ligands for certain
425
KIRs (such as 2DL1 and HLA-C2, 2DL2/2DL3 and HLA-C1, 3DL1 and HLA-Bw4). Specific KIR-HLA
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combinations present in certain individuals may play a critical role in determining the individuals’
427
immune status and predilection to disease (Single et al., 2008). Also, numbers of KIR genes and
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patterns of these genes make them a useful tool, just like HLA antigens, for analysing the genetic
429
background of susceptibility to human inflammatory, neoplastic, infectious disease and
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autoimmune disease (Kulkarni et al., 2008), including VKH disease (Levinson et al., 2008; Levinson
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et al., 2010; Sheereen et al., 2011). Though there was no evidence for a strong association of HLA
432
class I genes with VKH disease, KIRs and related HLA genes were assayed in 24 Mestizo patients
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with VKH disease from Southern California by Levinson et al (Levinson et al., 2008). No specific
434
genes were identified to be associated with VKH disease, but a trend of more haplogroups with
435
activating KIRs in patients (p=0.59) was observed (Levinson et al., 2008). In addition, some
436
inhibitory KIR-HLA combinations were more common in controls than in patients, though the
437
differences were not statistically significant. To eliminate the influence of genetic diversity on
438
data analysis within this study, Levinson et al (Levinson et al., 2010) conducted another study
439
examing whether the KIR genes could influence susceptibility to VKH disease in Japanese (26
440
patients and 173 controls). This sample was considered as a highly homogeneous population. The
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result showed a decreased freqency of 3DL1 (inhibitory KIR) (p=0.00006, OR=0.039) and an
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increased frequency of activating B haplogroups (p=0.01,OR=3.1) in patients when compared to
443
controls. Activating KIR genes 3DS1, 2DS1 and 2DS5 were more frequently seen in patients
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compared with controls (42.2% vs 21.4%, p=0.02). Most recently, KIRs and HLA-C alleles were
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typed for 30 patients with VKH disease and 125 controls from Saudi Arabia by Sheereen et al
(Sheereen et al., 2011). Results showed a significantly higher frequency of KIR2DS3, HLA-Cw*14,
HLA-Cw*17 and genotype Bx5 (one haplotype carrying two aKIRs, 2DS2 and 2DS4) in patients compared to controls. Among potential KIR-HLA interactions, the combination of inhibitory
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KIR2DL2/2DL3 and HLA-C1 was less frequently observed in VKH patients (p=0.018). Therefore,
450
certain KIRs may confer susceptibility to VKH disease in different populations, though
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disease-related KIRs, just like disease-related HLA antigens, were different depending on the
452
originating population. For a better understanding of the association of KIRs and VKH disease, 15
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more studies are needed to investigate the mechanisms how KIRs’ are involved in the regulation
454
of cells expressing these molecules (Natural Killer cells and some T lymphocytes ) and the
455
involvement of these cells in VKH disease.
456
Immunogenetics and VKH disease
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The association between the HLA system and KIRs with VKH disease does not fully explain the genetic risk for VKH syndrome. These genes play an important role in the antigen
459
presentation phase of the immune response, but other downstream pathways which have been
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shown to be polymorphic may also play a role in the genetic predisposition to VKH. Recently,
461
studies on the association of certain important functional genes (Fig 2) involved in the immune
462
response with this disease have further highlighted the genetic background of VKH disease
463
(Supplementary Table 2). Horie et al (Horie et al., 2006) were the first to hypothesize that
464
polymorphisms in the tyrosinase gene family loci could act as predisposing genes for VKH disease,
465
because tyrosinase-related proteins have been shown to be one of the autoantigens involved in
466
VKH disease (Yamaki et al., 2000a). They examined 7 microsatellite polymorphisms around the
467
loci for 87 patients with VKH disease and 122 healthy controls from Japan but found no
468
association between these polymorphisms and VKH disease. These results do not contradict the
469
critical role of tyrosinase-related proteins in VKH disease (Yamaki et al., 2000a), because a genetic
470
polymorphism in the autoantigen may not necessarily alter the immunogenic epitopes that
471
drives the autoimmune response directed to it. Polymorphisms of other genes controlling an
472
autoimmune response may on the other hand be involved in the susceptibility to VKH disease.
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We therefore started a series of studies addressing the role of polymorphisms of various
474
immunological pathways in the pathogenesis of VKH disease. One of our first studies included the
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analysis of four genetic polymorphisms of the cytotoxic T lymphocyte-associated antigen-4
(CTLA-4) gene, which encodes a critical negative regulator of the T cell-mediated immune response. We performed this study in 209 patients with VKH disease and 256 controls of Chinese
478
ethnicity (Du et al., 2008). The results showed significantly higher frequencies of the G allele at
479
the + 49 site (71.6% versus 62.8%, P = 0.0046, Pc = 0.037) and the haplotype − 1661A:− 318C:+
480
49G: CT60G (70.1% versus 60.0%, P= 0.0013, n= 16, Pc= 0.021) in patients than in healthy
481
controls (Du et al., 2008). Following these studies, Ohno’s group and our group performed a 16
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series of studies to investigate the association of several candidate genes with VKH disease in
483
Japanese and Chinese patients, including IFN-γ (Horie et al., 2007), SUMO4 (Hou et al., 2008),
484
PTPN22 (Horie et al., 2009; Zhang et al., 2014), FCRL3 (Li et al., 2009), PDCD1 (Meng et al., 2009),
485
STAT4 (Hu et al., 2010), IL-23R (Jiang et al., 2010b), IL-17 (Shu et al., 2010), OPN (Chu et al., 2011),
486
TLR9 (Ito et al., 2011), NLRP1 (Horie et al., 2011), CD40 (Chen et al., 2012a), TGFBR3 (Chen et al.,
487
2012b), miR-146a (Zhou et al., 2012), Ets-1 (Zhou et al., 2012), TNFAIP3 (Li et al., 2013b), JAK1
488
(Hu et al., 2013), FGFR10P (Yi et al., 2013), IL-12B, IL-12Rβ1/β2 (Li et al., 2014), DHCR7, CYP2R1,
489
CYP27B1, and CYP24A1 (Fang et al., 2014), TNIP1 (Kanda et al., 2014), TRAF5 and TRAF3IP2
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(Xiang et al., 2014), miR-182 (Yu et al., 2014), Bach2 (Gao et al., 2015) and CLEC16A (Li et al.,
491
2015) (Table 6). Studies on IFN-γ, PTPN22 and NLRP1 in Japanese and studies on SUMO4, IL-23R,
492
CD40, TGFBR3, miR-146a, Ets-1, Bach2 in Chinese failed to find an association with VKH disease.
493
Polymorphisms of FCRL3, JAK1, FGFR10P, PDCD1, STAT4, IL-17, IL-12B, OPN, TNIP1, TRAF5,
494
TRAF3IP2, miR-182, PTPN22 and CLEC16A, on the other hand have been shown to be associated
495
with VKH disease in Chinese patients. These studies partially confirm the hypothesis that
496
polymorphisms of genes involved in the immune response confer susceptibility to VKH disease
497
and broaden our understanding of the genetic background of this disease.
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In addition to microsatellites and SNPs, recently, copy number variations (CNVs), which are characterized by insertions, deletions, and duplications of genomic sequences ranging from a
500
kilobase to multiple megabase-long pairs, also have been demonstrated as one of the important
501
genetic markers for diseases with complex traits. We employed CNVs as a genetic marker to
502
further assess the association of immune related genes with VKH disease (Supplementary Table
503
3). We firstly evaluated the association of complement 4 (C4) with VKH disease using CNVs as a
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genetic marker. Our results demonstrated that lower CNVs of the C4 gene confer risk for VKH syndrome, which may be caused by a decreased expression of the C4 gene in those patients (Hou
et al., 2014b). Subsequently, we assessed the relationship of complement components (C3, C4,
C5, C6, C7, C8A, C8B and C9) (Hou et al., 2014b), Toll-like receptors (TLR1-3, TLR5-7, TLR9 and
508
TLR10) (Fang et al., 2015), key transcription factors for differentiation of CD4+ T cell (TBX21,
509
GATA3, RoRγ and Foxp3) (Liao et al., 2015), genes involved in the IL-17/IL-23 pathway (IL17A,
510
IL17F, IL23A and IL23R) (Hou et al., 2015) and genes related to apoptosis (FAS, CASPASE8,
511
CASPASE3, and BCL2) (Yu et al., 2015). Higher copy numbers of C3, C4, IL-17F, IL-23A and FAS 17
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have been shown to be associated with VKH disease and the association may be partly explained
513
by the different gene expression profiles that are dependent on the gene copy number
514
(Supplementary Table 3). Interestingly, several genes predisposing to VKH disease, including IL-12B (Li et al., 2014);
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MIF (Zheng et al., 2012); TNFAIP3 (Li et al., 2013a); TRAF5 and TRAF3IP2 (Xiang et al., 2014);
517
IL17F and IL23A (Hou et al., 2015); C3 (Xu et al., 2015) and FAS (Yu et al., 2015), have also been
518
shown to be associated with Behcet’s disease, another common immune-mediated panuveitis in
519
China, though the specific disease-associated alleles in the same gene may be different for the
520
two diseases. These results indicated a common genetic basis between two immune-mediated
521
panuveitis entities. Genetic variations which mediate the immune response have been proposed
522
as common disease-associated genetic factors (Burton et al., 2007; Parkes et al., 2013;
523
Zhernakova et al., 2009). However, some diseases may be associated with unique disease-specific
524
genetic factors. Genome-wide association studies (GWAS) on VKH disease may provide more
525
insight into the role of genetic factors, both the common disease associated genetic factors and
526
VKH disease specific genetic factors in this disease. Our recent GWAS on VKH disease indeed
527
identified three loci associated with VKH disease susceptibility: IL23R-C1orf141,
528
ADO-ZNF365-EGR2 and HLA-DRB1/DQA1 (Hou et al., 2014a). The IL23R-C1orf141 and
529
HLA-DRB1/DQA1 loci were two of the common genetic factors that are also shared with other
530
immune-mediated diseases (Parkes et al., 2013; Zhernakova et al., 2009). The VKH disease
531
specific SNP rs442309 did not affect the expression of the genes ADO, ZNF365 and EGR2 in this
532
region (Hou et al., 2014a). Our GWAS study thus confirmed the role of HLA-DRB1/DQA1 as a
533
specific predisposing genetic factor to VKH disease while it failed to find new VKH disease specific
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predisposing genetic factors. More recently, we conducted a candidate genes association study
for VKH disease in multinational populations, including Chinese Singaporeans, non-Han Chinese,
Thailand and Koreans. Our results confirmed the genetic associations between SNPs in
IL23R-C1orf141 and VKH syndrome in Chinese Singaporeans but not in other Asian populations (in press). Based on the analysis above, limitations in immunogenetic studies are obvious. Firstly, the
540
associations identified using SNPs or CNVs were moderate and to date most of them were
541
reported for VKH patients from China. Replication of these associations in different populations is 18
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required. Secondly, because of the linkage equilibrium, most of the VKH disease associated
543
genetic markers, including SNPs, are probably not the true causative factors for the disease.
544
Novel methods to identify the real causative genetic factors for VKH associated genetic markers
545
are necessary to make further progress in the field. Thirdly, one should keep in mind that genes
546
interact with each other and to date most studies only focus on the role of single genes and do
547
not yet account for gene networks in the predisposition to disease.
548
Pathology
Historically, VKH disease is primarily considered as a non-necrotizing diffuse
SC
549
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granulomatous inflammation of the uveal tract similar to sympathetic ophthalmia. Pathological
551
features were characterized by the presence of nodular lesions consisting of epithelioid cells
552
surrounded by a wall of lymphocytes and plasma cells (Ikui and Mimura, 1970; Ikui et al., 1959).
553
The origin of the epithelioid cells, which have been extensively studied in eyes with sympathetic
554
ophthalmia, were believed to be altered melanocytes (Ikui and Mimura, 1970; Miura and Ikui,
555
1970) or derived from monocytes and histiocytes (Matsuda, 1970). However, an
556
immunohistochemical study performed by Rao et al (Rao et al., 1985) demonstrated that these
557
epithelioid cells showed a positive staining with muramidase, S-100 protein and binding of
558
peanut lectin suggesting that the cells could be identified as tissue macrophages.
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According to early studies, the choriocapillaris, the retinal pigment epithelium and retina are usually spared during the early stage of VKH disease partly due to the possible role of RPE
561
cells in suppressing inflammation (Rao, 1997). However, with the progress of the disease,
562
granulomatous choroiditis with damage of the choriocapillaris, depigmentation, pigment
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dispersion and pigment phagocytosis is prominent at the chronic recurrent stage of the disease. Recently, Spectral-Domain Optical coherence tomography (SDOCT) provided non-invasive high
speed, high resolution, three-dimensional cross-section imaging of the RPE changes
(Vasconcelos-Santos et al., 2010). Observations by SDOCT have demonstrated that even at the
567
early stage, RPE cells are severely affected, presenting as folds of RPE (Lin et al., 2014; Tsuboi et
568
al., 2015). At the convalescent stage of VKH, the choroid is significantly thinner and the
569
choriocapillaris layer is disrupted (Nazari et al., 2014). Evaluation of the choriocapillaris in SD-OCT
570
scans may be a useful tool for evaluating the degree of disease severity and may also be helpful 19
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in predicting the prognosis of VKH disease. Another typical histologic feature in VKH disease are the Dalen-Fuchs nodules. They
573
usually manifest as a hemispherical mound between the RPE and Bruch’s membrane consisting of
574
lymphocytes, macrophages, epithelioid cells, and proliferated RPE cells (Reynard et al., 1985).
575
Clinically, the depigmented, small, round to oval lesions appearing at the chronic stage of disease
576
were considered to represent Dalen-Fuchs nodules. However, a histopathologic study by Inomata
577
et al (Inomata and Rao, 2001) have shown that these clinically visible lesions represent locally
578
damaged or disappeared retinal pigment epithelial cells, not corresponding to the
579
histopathological Dalen-Fuchs nodules. In addition, Inomata et al (Inomata and Rao, 2001) have
580
shown that Dalen-Fuchs nodules are made up of mainly lymphocytes and macrophages in the
581
early stage and a group of proliferated retinal pigment epithelial cells with few inflammatory cells
582
at the convalescent stage.
583
Immunopathology
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Immunohistochemical studies on eyes of patients with VKH disease lay the first stone for the basis of cells and molecules responsible for the immune response involved in the ocular
586
inflammation leading to VKH disease. Some of the early studies were hampered by the fact that
587
only morphological criteria were used to identify immune cells but were later expanded by using
588
monoclonal antibodies to determine the cellular subtypes (Sugiura and Matsuda, 1971). Inomata
589
et al (Inomata and Sakamoto, 1990) examined 4 eyes obtained from two patients with VKH
590
disease (one died 32 months after the onset of VKH and the other died 7 years after onset) and
591
observed a scattered infiltration of lymphocytes in a thickened choroid with a remarkable
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disappearance of choroidal melanocytes by immunohistochemistry. Furthermore, T and B lymphocytes were identified by immunohistochemical methods with monoclonal antibodies.
Approximately 70% of the lymphocytes were identified as T cells (Inomata and Sakamoto, 1990).
The results confirmed previous reports by Chan et al (Chan et al., 1988). Sakamoto et al
596
(Sakamoto et al., 1991) also confirmed that the choroidal infiltrate was composed predominantly
597
of T lymphocytes with a larger proportion of helper T cells than suppressor/cytotoxic T cells. In
598
addition, choroidal melanocytes and the endothelium of the choriocapillaris were found to
599
express HLA class II antigens. With the close contact between lymphocytes and melanocytes 20
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found previously (Sugiura, 1976b; Sugiura and Matsuda, 1971), these results indicated that
601
cell-mediated immune mechanisms may play an important role in the development and
602
progression of VKH disease. The cell mediated immune response can cause irreversible damage
603
to the fragile ocular structures and may induce neovascularization, thereby contributing to ocular
604
tissue damages in VKH. This is supported by current observations showing that biologic agents
605
specifically suppressing the cell mediated response (anti-TNF, Interferon alpha) or neovascular
606
response (anti-VEGF) are so effective in VKH management. This subject will be discussed in more
607
detail in the therapy section shown below.
608
Antigens
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Soon after the description of VKH, pigment was already thought to play an antigenic role in
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its development. Since the demonstration of hypersensitivity to uveal pigment in patients with
611
VKH disease with a skin test (McPherson and Woods, 1948), a number of studies were conducted
612
to identify the antigens as well as antibodies in patients with VKH disease (Hammer, 1971; Kudo,
613
1969; Wong et al., 1971). Compelling evidence for the central role of melanocytes in the
614
development of VKH disease came from a study reported by Lambe et al (Lambe et al., 2006). In
615
this study, a spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris
616
and Vogt-Koyanagi-Harada syndrome was induced in “double” transgenic mice. Transgenic mice
617
expressing hen egg lysozyme as a melanocyte-specific neoantigen were crossed with transgenic
618
animals expressing a CD4 T cell receptor specific for hen egg lysozyme. Depigmentation became
619
evident in the ears at 21 days of age, and as the animals grew older, it mainly affected the eyes,
620
genitalia, and the skin on the back and abdomen. This model provides further support for the
621
role of CD4+ T cells directed against melanocyte associated antigens in the pathogenesis of VKH.
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Until now, the most studied antigens implicated in the development of VKH disease are the
melanocyte-related proteins. Based on the concept that melanoma antigens are also molecules involved in
625
melanocyte-related autoimmune disease, such as VKH disease and sympathetic ophthalmia,
626
Sugita et al (Sugita et al., 1996) investigated whether the MART-1 antigen, one of the several
627
antigens identified on melanomas and melanocytes, was the target involved in VKH disease. CD8+
628
T cell clones isolated from the intraocular fluid of patients with VKH disease lysed melanocytes in 21
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629
a HLA-A2+-restricted manner, whereas neither CD8+ T cell clones from patients with Behcet’s
630
disease nor HTLV-1 uveitis showed this cytotoxicity. These results suggested that VKH disease
631
might be an autoimmune disease directed towards the MART-1 antigen in HLA-A2+ patients. Yamaki et al (Yamaki et al., 2000a) found that T-lymphocytes obtained from patients with
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VKH disease showed a significant stimulation following incubation with tyrosinase related protein
634
(TRP) 1 and TRP 2. These authors hypothesized that VKH disease was an autoimmune disease
635
directed against these two specific antigens. In addition, they also immunized Lewis rats with
636
either TRP1 or TRP2 in the presence of complete Freund’s adjuvant and developed an
637
inflammatory disease resembling VKH disease clinically and histologically (Yamaki et al., 2000b).
638
Synthetic peptides derived from tyrosinase, TRP1, TRP2 and Pmel17 were found to be specifically
639
recognized by peripheral blood mononuclear cells (PBMCs) of HLA-DRB1*0405-positive patients
640
with VKH disease (Damico et al., 2005a). These results provided evidence for the involvement of
641
tyrosinase family proteins in the development of VKH disease as a specific antigen, although the
642
precise mechanisms involved need further clarification.
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Several other melanocyte-related antigens and other antigens have also been proposed to be involved in VKH disease, such as antigens from photoreceptors and Müller cells(Chan et al.,
645
1985), gp-100/PMel-17 (Chan et al., 1998), lens epithelium derived growth factor (LEDGF)
646
(Yamada et al., 2001b), and uveal autoantigen (UACA) (Yamada et al., 2001a). Identification of
647
antibodies against the antigen KU-MEL-1 and PAX3 in patients with VKH disease suggests that
648
these two antigens may also be involved in VKH disease (Matsuzaki et al., 2005; Otani et al.,
649
2006). Novel techniques to analyze peptide interactions with HLA class II molecules using high
650
throughput in silico methods were recently developed to identify immunogenic peptides in
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patients with VKH disease (Prasad and Levinson, 2005). As yet however, the causative peptide has
not yet been identified. Immune responses
As mentioned above, it has long been thought that autoimmune responses to melanin
655
may be the underlying process responsible for the lesions in multiple organs of patients with VKH
656
disease. Earlier studies demonstrated that lymphocytes from patients with VKH disease were
657
sensitized to uveal pigment as shown by various in vitro assays such as the lymphocyte 22
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transformation test (Hammer, 1971; Yuasa et al., 1975), leukocyte migration inhibition test
659
(Hammer, 1974; Sanefuji, 1974; Yuasa et al., 1975) and lymphocyte-mediated cytotoxicity test
660
(Tagwa, 1978). Studies on peripheral blood lymphocytes (PBL) performed by Maezawa et al
661
(Maezawa and Yano, 1984; Maezawa et al., 1982) identified two distinct cytotoxic lymphocytes
662
(CD4+ and CD8+) against human melanoma cells and melanocytes and these results reinforced
663
the important role of T cells in VKH disease. Analysis of surface markers on lymphocytes by laser
664
flow cytometry showed alterations in total numbers of T cells and their subpopulations (Liu and
665
Sun, 1993; Okubo et al., 1985). Norose et al(Norose et al., 1990) demonstrated a higher ratio of
666
OKT4+/8+ cells (CD4/CD8) in CSF from patients with VKH than in their peripheral blood. These
667
earlier studies suggested that certain subpopulations of T cells play a role in the development of
668
VKH disease.
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In the 1990’s, the wide acceptance of experimental autoimmune uveitis (especially in mice) as a model of VKH disease and extensive studies using this model have shed further light on the
671
immune responses involved in the development of VKH disease (Caspi et al., 1988; Gery et al.,
672
1986). T cells (Th1, Th17, γδ T cells and regulatory T cells), macrophages and neutrophils have
673
been extensively studied using the EAU model and their roles have been extensively reviewed
674
elsewhere (Kerr et al., 2008; Mochizuki et al., 2013). Due to the difficulty in collecting local
675
samples (such as aqueous humor or inflamed choroid) from the affected eyes, little is known
676
about the exact immune response in the human eye, though studies have demonstrated a great
677
difference in the in vitro immune responses between cells obtained from the aqueous humor as
678
compared to peripheral blood lymphocytes (Kitaichi et al., 2007). However, as a disease affecting
679
multiple organs, studies on PBLs may still shed light on the immune responses involved in this
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disease. This section aims to review studies regarding immune cells in VKH disease, especially T
cells and related cytokines. After priming with autoantigens (such as melanocyte-related antigens) or exogenous
peptides simulating the autoantigens (such as CMV-egH290-302 discussed in the following section),
684
naïve T cells differentiate into effector T cells: type 1 helper T (Th1) cells, Th17 cells and others. If
685
the immune responses initiated by these cells cannot be suppressed by natural regulatory T cells
686
(nTregs) generated in the thymus (Sakaguchi and Sakaguchi, 2005), autoimmune responses will
687
occur in multiple organs, including the eyes. We assayed the peripheral blood CD4+CD25high Treg 23
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cells phenotypically and functionally in patients with VKH disease with active uveitis (Chen et al.,
689
2008). CD4+CD25highTreg cells from patients with active VKH showed a significant deficiency in
690
suppressing the proliferation of CD4+CD25- T cells and in inhibiting the production of IFN-γ and
691
IL-13 by CD4+CD25- T cells, but not IL-17 production. These results suggested that the
692
development of VKH disease may partially be due to quantitatively abnormal and functionally
693
diminished CD4+CD25high Treg cells in susceptible individuals. Commodaro et al (Commodaro et
694
al., 2010) analyzed nTregs defined as CD25high Foxp3+ in patients with VKH disease and found no
695
difference in the CD4+CD25high and CD25high Foxp3+ T cells when compared to healthy controls.
696
The discrepancy may come from the different definition of nTregs in these two studies. Unlike the
697
recurrent inflammation in VKH disease, uveitis in the EAU model usually presents as a
698
self-limiting monophasic process. Earlier we found that nTregs increased significantly with the
699
development of the EAU, suggesting that increased nTregs in EAU induced in mice with normal
700
immune regulatory capacity may be partially responsible for the monophasic nature and rapid
701
regression of EAU (Sun et al., 2010). These conflicting results between VKH syndrome and the
702
EAU model further demonstrated the critical role of regulatory T cells in the maintenance of the
703
ocular immune balance and in the regression of uveitis.
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Besides our observation that regulatory T cells may be functionally defective in patients with VKH, subsequent studies have focused on a possible role for immunoregulatory cytokines in
706
the development of the disease. Commodaro et al (Commodaro et al., 2010) compared the level
707
of IL-10 (which considered as a product of T regulatory type 1 cells) and TGF-β (which is
708
considered as a product of Th3 regulatory cells) in healthy controls and in active and inactive VKH
709
patients in cell culture supernatants of peripheral blood mononuclear cells stimulated with
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phytohaemagglutinin. They found that TGF-β and IL-10 were increased in patients with VKH in the inactive stage of the disease and suggested that these cytokines were associated with the resolution phase of the disease. They found no differences in the frequency of regulatory T cells
in these three groups and concluded that immunoregulatory cytokines are probably more
714
important in controlling the disease. As mentioned above, the discrepancy concerning the role of
715
regulatory T cells in VKH may be due to a different definition in the terminology of regulatory T
716
cells (Chen et al., 2008). A compromised function of regulatory T cells has also been noted in
717
other immune mediated disorders such as rheumatoid arthritis and was shown to be corrected 24
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718
following anti-TNF therapy (Ehrenstein et al., 2004). The effect of anti-TNF therapy on regulatory
719
T cell populations in VKH have not yet been reported and remain an interesting subject for future
720
studies on the role of these cells in the pathogenesis of this disease. In addition to aforementioned studies on the pathology and immunopathology of VKH
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disease, the contribution of effector T cells to this disease has been evidenced by the dominance
723
of activated T cells in aqueous humor (Norose et al., 1994; Ohta and Yoshimura, 1998) and CSF
724
during the acute phase (Norose et al., 1990). To explain the local increase of T cells, studies have
725
been directed towards the role of apoptosis-related Fas markers on memory T cells in aqueous
726
humor and peripheral blood during VKH disease (Ohta and Yoshimura, 1998; Yang et al., 2002;
727
Yang et al., 2001) in view of the fact that the Fas-Fas-ligand system has been demonstrated to be
728
important in mediating apoptosis of immune cells and maintaining ocular immune privilege
729
(Griffith et al., 1995). These studies showed an increased expression of Fas in aqueous humor,
730
CSF and peripheral blood from patients with VKH disease (Ohta and Yoshimura, 1998). However,
731
resistance of lymphocytes to Fas-mediated apoptosis in VKH disease suggested that long-lived
732
lymphocytes may contribute to the increase of T cells and the development of uveitis (Yang et al.,
733
2002; Yang et al., 2001).
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Th1 cells were the first subtype of T cells shown to be involved in the development of VKH disease. A number of studies addressed the role of Th1 cells and the associated cytokine profile
736
(such as IL-12, IFN-γ and IL-6) in VKH by analyzing aqueous humor, CSF and peripheral blood
737
(Andreoli and Foster, 2006; Imai et al., 2001; Miyazawa et al., 2005; Norose and Yano, 1996).
738
T-bet is considered as the critical transcriptional factor for Th1 cells and Li et al (Li et al., 2005)
739
assayed the level of T-bet, IFN-γ, IL-2 and IL-4. An up-regulated expression of T-bet and IFN-γ was
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found in patients with VKH disease (Li et al., 2005). These results support a role of Th1 cells in the
development of VKH disease. Th17 cells, which typically produce IL-17 by stimulation through IL-23, have also been
shown to contribute to the development of VKH disease (Chi et al., 2007; Jiang et al., 2010a).
744
Studies from our group on this subject showed an increased expression of IL-23 p19 mRNA in
745
peripheral blood mononuclear cells (PBMCs), higher levels of IL-23 in serum and supernatants of
746
PBMCs, and an increased level of IL-17 by polyclonal stimulated PBMCs and CD4+ T cells in
747
patients with active VKH (Chi et al., 2007). These results indicated that activation of the 25
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IL-23/IL-17 pathway was involved in the development of VKH disease. Further studies
749
demonstrated that production of IL-17 by polyclonal stimulated PBMCs and CD4+ T cells was
750
significantly enhanced by recombinant IL-23 and that IL-17 production by these activated cells
751
stimulated with IL-23 was significantly higher in patients with active VKH disease than in patients
752
with inactive VKH disease and in normal controls. It should be noted that many other cell types,
753
such as natural killer T (NKT) and innate lymphoid cells (ILC) can also produce IL-17. Therefore
754
levels of this cytokine do not necessarily correlate with Th17 cells numbers. An interesting
755
observation was the finding that IL-12 and IFN-γ, both of which were considered as Th1 cytokines,
756
significantly suppressed the production of IL-17 by polyclonal stimulated PBMCs and CD4+ T cells
757
(Chi et al., 2007). In addition, rIL-23, which is the growth and stabilization factor for Th17 cells,
758
enhanced IFN-γ production. These results demonstrated that both Th1 cells (IL-12/IFN-γ pathway)
759
and Th17 cells (IL-23/IL-17 pathway) were involved in the development of VKH disease.
760
Furthermore, these two cell types maybe regulated by the same cytokines.
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When summing up the evidence reviewed above, a hypothetical network involved in the
762
development of VKH disease can be constructed. This network is composed of different kinds of
763
effector cells, including Th1 cells, Th17 cells and nTregs. Besides cells, a number of soluble factors
764
such as cytokines, chemokines and transcription factors are also involved in the network. During
765
the development and progress of VKH disease, these factors may interact with each other
766
directly or indirectly. In turn, the network becomes more and more complicated. Our recent
767
studies provided ongoing evidence for the complicated network that may be operative in the
768
pathogenesis of VKH. Cytokines (such as IL-7 IL-21, IL-27, IL-25and IL-37) (Li et al., 2010; Wang et
769
al., 2012; Xu et al., 2014; Yang et al., 2012; Ye et al., 2015), leptin (Liu et al., 2008), osteopontin
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(Chu et al., 2011), 1,25-Dihydroxyvitamin D3 (Yi et al., 2011), interleukin-1 receptor-associated
kinases (IRAK) (Sun et al., 2014) and liver X receptor (Wu et al., 2014)have been demonstrated to
be involved in the development of VKH disease by regulating the IL-23/IL-17 pathway and/or Th1
cells.
It should be noted that RPE cells may also play an important role in this network, not only
775
because they are the target of immune responses, but also because they are involved in the local
776
regulation of immune homeostasis in the posterior segment of the eye. One of our studies
777
demonstrated that ARPE-19 cells, a spontaneously arisen cell line of RPE, constitutively expressed 26
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IL-17RC and IL-22R (Chen et al., 2011). Furthermore, IL-17A and IL-17F significantly enhanced the
779
production of inflammatory cytokines, such as CXCL8, CCL2, CCL20 and IL-6 by these cells (Chen
780
et al., 2011). Both IL-17A and IL-17F significantly decreased the transepithelial electrical
781
resistance (TER) of the ARPE-19 monolayer and increased the diffusion rate of fluorescein
782
isothiocyanate (FITC)-dextran. Whether the RPE layer is damaged due to the destruction of the
783
underlying choroidal capillaries thereby limiting access of necessary nutrients or due to a direct
784
autoimmune attack of RPE melanin remains to be studied.
785
Triggering factors
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Though it is now accepted that VKH disease is an autoimmune disease, a triggering role of infection leading to this disease is still a widely believed concept. The acute onset and
788
self-limiting nature of symptoms, such as a slight fever, headache and fatigue during the
789
prodromal stage of VKH disease suggests a microbial infection before its onset. Epstein-Barr virus
790
(EBV) DNA has been detected in cerebrospinal-fluid from patients with Vogt-Koyanagi-Harada
791
disease using the PCR method (Usui et al., 1991), but these findings could not be confirmed by
792
other groups(Saito et al., 1993). A more direct evidence for the involvement of a virus in VKH
793
disease was the identification of EBV DNA in the vitreous from a patient with VKH disease (Bassili
794
et al., 1996). However, EBV is a ubiquitous virus in humans and a case report may not be
795
considered as formal proof of a role of EBV in VKH. A further study showed that B lymphocytes
796
from VKH patients were more susceptible to EBV activation than those from patients with other
797
uveitis entities (Minoda et al., 1999). The proposed mechanism of action suggests a resemblance
798
between virus-associated proteins and autoantigens in VKH disease. According to the
799
cross-reaction and molecular mimicry theories, the similarity between exogenous antigens
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(produced by pathogenic microorganisms) and host proteins will cause an immune response
(which should be constricted to eliminate organisms) to host proteins (Oldstone, 1987). Viruses, especially retroviruses, may encode antigens that resemble host proteins. Sugita et al (Sugita et
803
al., 2006) found six amino acids with the anchor position of HLA-DRB1*0405 shared by
804
tyrosinase450-462 (peptide derived from host proteins) and cytomegalovirus envelope glycoprotein
805
H290-302 (CMV-egH290-302) (a cytomegalovirus-associated peptide). Furthermore, they isolated
806
several T cell clones that responded strongly to CMV-egH290-302 as well as to the tyrosinase450-462 27
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807
peptide (Sugita et al., 2007). These studies suggest that viral infections may trigger the
808
autoimmune response underlying VKH disease through a mechanism of molecular mimicry.
809
The need for an adjuvant in the experimental autoimmune uveitis model, which is widely accepted as a useful model for VKH disease, also supports the triggering role of infectious agents
811
in uveitis. Toll-like receptors (TLRs) are a large family of so called pattern-recognition receptors
812
(PRRs)(Kawai and Akira, 2010). Their activation by recognizing a variety of microbial immune
813
components will initiate the consequent innate immune response and shape the adaptive
814
immune responses. With the identification of TLRs in the human uveal tract (Chang et al., 2006;
815
Rodriguez-Martinez et al., 2005), the evidence for a potential role of TLRs in the pathogenesis of
816
uveitis increased rapidly (Allensworth et al., 2011; Chang et al., 2007; Fang et al., 2010). However,
817
most studies on the role of TLRs in uveitis have focused on anterior uveitis. A recent study from
818
our group showed that the macrophage expression of TLR3 and TLR4, but not TLR2, was
819
significantly increased in active VKH patients as compared to controls (Liang et al., 2015). Gene
820
variants of TLR2, TLR4, TLR8, and TLR9 were however not shown to be associated with VKH
821
disease (Fang et al., 2013; Ito et al., 2011).
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Other intracellular pattern recognition receptors include the so called Nucleotide-binding
823
oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2), which recognize bacterial
824
products and upon ligand binding result in an immune reaction. We recently examined the
825
expression of NODs in patients with active VKH syndrome and found a higher expression of NODs
826
on PBMCs as compared with controls (Deng et al, manuscript in preparation). Furthermore,
827
activation of NODs with their natural ligands iE-DAP or MDP markedly increased the level of
828
proinflammatory cytokines by PBMCs and DCs. Activation of NODs in DCs may also promote the
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differentiation and proliferation of CD4+T cells. Taken together these findings indicate that PRRs,
such as NODs, may be involved in the pathogenesis of VKH syndrome (Deng et al. manuscript in
preparation). Further studies are required to provide new insights on the potential role of PRRs in bridging a possible role of a microbial infection in the prodromal stage of VKH disease and the
833
ensuing innate immune response leading to a chronic, adaptive autoimmune melanocyte attack
834
in multiple organs.
835
Clinical features 28
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836 837
Stage of VKH disease The most frequent complaint in patients with VKH disease is a rapid decrease in vision in one or both eyes following a transiently blurred vision. Other complaints include red eyes, eye
839
pain or orbital pain and floaters (Moorthy et al., 1995; Yang et al., 2007). According to the clinical
840
features, the course of VKH is typically classified in four consecutive stages: prodromal stage,
841
acute stage, chronic convalescent stage and chronic recurrent stage (Moorthy et al., 1995;
842
Rajendram et al., 2005; Read et al., 2001c).
843
Prodromal stage
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The prodromal stage usually lasts for 1 to 2 weeks and is characterized by flu-like symptoms. Prodromal symptoms are nonspecific, including headache, tinnitus, nausea, neck and
846
back stiffness, and an abnormal sensitivity to touch of the hair (Moorthy et al., 1995; Rajendram
847
et al., 2005; Rao et al., 2010). Periorbital pain is not rare (Han et al., 2010). The auditory
848
disturbances such as tinnitus and dysacusis also occur in this stage. Rare neurologic signs,
849
including cranial nerve palsies and cerebellar or psychiatric signs have also been described
850
(Andreoli and Foster, 2006; Moorthy et al., 1995). Pleocytosis in CSF can be found by lumbar
851
puncture at this stage and this sign can last up to 8 weeks (Read et al., 2001c).
852
Acute stage
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The acute stage begins with the occurrence of acute uveitis, typically bilateral posterior uveitis (Moorthy et al., 1995; Rajendram et al., 2005). This stage usually continues for several
855
weeks. Either choroiditis or chorioretinitis of a nongranulomatous nature is the most prominent
856
finding within the first 2 weeks (Rao et al., 2010; Yang et al., 2007). The anterior segment is
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854
spared from inflammation during these 2 weeks, though mild anterior chamber flare can be
observed in some patients. In Chinese patients with VKH disease, we define this stage as the
posterior uveitis stage because inflammation is limited to the posterior segment of the eye (Yang
860
et al., 2007). A sudden decrease in vision in both eyes is the most often mentioned complaint at
861
this stage. The visual acuity varies from light perception to more than 20/40 (Rubsamen and Gass,
862
1991; Yang et al., 2007). In the majority of patients, both eyes are affected simultaneously.
863
According to observations, the interval from uniocular to binocular involvement ranged from 1 to 29
ACCEPTED MANUSCRIPT
2 weeks, mostly occurring within 7 days (Chi et al., 2007; Moorthy et al., 1995; Rajendram et al.,
865
2005). Unilateral ocular involvement in patients with presumed VKH disease has been noted
866
during a disease follow up of 16 years (Usui et al., 2009). Multiple exudative retinal detachment
867
(ERD) (Fig 3), optic disc swelling and thickening of the posterior choroid with slight involvement
868
of vitreous body are the typical signs at the acute stage (Moorthy et al., 1995; Rajendram et al.,
869
2005; Yang et al., 2007). ERD, typically multiple and localized to the posterior pole and/or the
870
midperiphery, is present in over 85% of cases (da Silva et al., 2009a; Keino et al., 2006; Yang et al.,
871
2007). A multicenter study including different ethnic groups of patients with bilateral acute VKH
872
uveitis has shown that bilateral ERD during the acute stage is a highly specific sign for this entity
873
(Rao et al., 2010). Optic disk hyperemia or edema can be found in 69% to 87% of cases
874
(Bordaberry, 2010; Yang et al., 2007). The occurrence of disk edema has been shown to be
875
associated with age and disc morphology (Nakao et al., 2012). Furthermore, the optic disc edema
876
may lead to visual field defects in patients by ischemic damage (Nakao et al., 2012; Nakao et al.,
877
2009). Round, white-yellowish lesions of variable size, located in the posterior or midperipheral
878
fundus (Moorthy et al., 1995) and choroidal folds in the posterior pole are also common signs
879
during the acute stage (Wu et al., 2007; Zhao et al., 2009).
TE D
M AN U
SC
RI PT
864
Involvement of the anterior segment ensues if the disease is not well controlled,
881
presenting as mild to moderate anterior uveitis with a nongranulomatous nature. This stage is
882
defined as the anterior uveitis stage in our classification (Yang et al., 2007). Signs suggesting
883
granulomatous inflammation, such as mutton fat keratic precipitates on the corneal endothelial
884
surface or Koeppe and Busacca nodules in the iris are rarely present (Yang et al., 2007).
885
Occasionally, manifestations resembling acute angle closure glaucoma, such as a shallow anterior
887 888
AC C
886
EP
880
chamber and increased IOP, may be present in certain individuals because of ciliary body edema
secondary to the inflammation (Yang et al., 2011; Yao et al., 2013).
Chronic (convalescent) stage
889
According to studies reported previously, a chronic convalescent stage occurs several
890
weeks after the acute stage and continues for months or even years (Rajendram et al., 2005).This
891
stage is characterized by signs of depigmentation in integumentary and/or uveal tissue. Sunset
892
glow fundus is the most common sign resulting from depigmentation of the choroid at this stage 30
ACCEPTED MANUSCRIPT
(Yang et al., 2007). It has been shown to be very specific to VKH disease in the setting of chronic
894
bilateral uveitis and is useful for its diagnosis (Rao et al., 2010). Nummular chorioretinal scars
895
presenting as well-defined oval or round areas in the midperiphery of the fundus is another
896
common sign for VKH disease (Rao et al., 2010; Yang et al., 2007). Poliosis of the eyebrows or
897
eyelashes, alopecia and vitiligo are the most common signs of depigmentation occurring during
898
the chronic stage (Rao et al., 2010; Yang et al., 2007). Other signs of disturbance in pigmentation
899
include the so called Sugiura sign (depigmented limbus), peripheral iris depigmentation and RPE
900
clumping/migration (Attia et al., 2007; Friedman and Deutsch-Sokol, 1981; Rao et al., 2010). The
901
Sugiura sign is rarely seen in other populations than from Japanese descent (Friedman and
902
Deutsch-Sokol, 1981). RPE clumping/migration are among the most common signs in the chronic
903
stage of VKH disease (Rao et al., 2010).
904
Chronic recurrent stage
SC
M AN U
905
RI PT
893
The chronic recurrent stage is characterized by a mild panuveitis with recurrent episodes of anterior uveitis. This stage is usually considered to be the result of inadequate or delay of
907
treatment with corticosteroids for the disease (Moorthy et al., 1995; Rajendram et al., 2005).
908
With the recurrence of anterior uveitis, the inflammation gradually changes from
909
nongranulomatous to a granulomatous nature. Mutton fat keratic precipitates on the corneal
910
endothelial surface and flare and cells in the anterior chamber are the typical features of this
911
stage. Koeppe and Busacca nodules in the iris are not uncommon in the recurrent stage (Rao et
912
al., 2010; Yang et al., 2007). Iris atrophy and depigmentation may also be seen (Attia et al., 2007;
913
Moorthy et al., 1995). However, recurrent posterior uveitis with exudative retinal detachment,
914
optic disc swelling and vitritis are less common (Andreoli and Foster, 2006; Yang et al., 2007).
916 917
EP
AC C
915
TE D
906
Most of the ocular complications, such as cataract, glaucoma, choroidal neovascular
membranes and subretinal fibrosis develop during this stage. Complicated cataract is the most
frequent complication and subretinal fibrosis is the most severe complication (Moorthy et al.,
918
1995; Yang et al., 2007). A recent study demonstrated that VKH disease was the third primary
919
specific type of uveitis causing inflammatory CNV in China (Wu et al., 2015).
920 921
The rate of ocular complications has been shown to be associated with the number of recurrences of inflammation and to the duration of the disease (Read et al., 2001c). 31
ACCEPTED MANUSCRIPT
922 923
Staging system in the Chinese population The staging system of VKH disease as discussed above has now been widely accepted, because more consideration has been given to the process of VKH disease as well as the
925
accompanying immune response. This staging system embodies the natural history of VKH
926
disease. However, the boundary between the chronic convalescent stage and the chronic
927
recurrent stage is still obscure, especially for patients in the chronic recurrent stage only showing
928
anterior nongranulomatous uveitis. Therefore, we would like to propose an alternative staging
929
system that also includes 4 stages but which emphasizes the evolutionary processes based on a
930
study of 410 consecutive Chinese VKH patients. It consists of a prodromal stage (about 1 or 2
931
weeks before uveitis onset), a posterior uveitis stage (about 2 weeks after uveitis onset), an
932
anterior uveitis stage (from 2 weeks to 2 months after uveitis onset) and a recurrent
933
granulomatous anterior uveitis stage (more than 2 months after uveitis onset). We believe that
934
our staging system is much simpler for diagnosis. In addition, this system pays more attention to
935
the dynamic changes in the anatomical location in the eye and the nature of the inflammation.
936
The intraocular inflammation observed in Chinese patients with VKH proceeds from the posterior
937
segment to the anterior segment and from a nongranulomatous to a recurrent or chronic
938
granulomatous nature if the disease was not properly controlled therapeutically (Yang et al.,
939
2007). It is noteworthy that not all patients with VKH disease go through all 4 stages. Appropriate
940
management can halt the disease at either the posterior uveitis stage or the anterior uveal
941
involvement stage (Chee et al., 2007; Rajendram et al., 2005; Yang et al., 2007).
942
Complications
944 945 946 947
SC
M AN U
TE D
EP
AC C
943
RI PT
924
Approximately half of the patients and half of the eyes develop at least one complication
(Read et al., 2001c). Cataract, glaucoma, subretinal fibrosis and choroidal neovascularization are
the most common complications seen in VKH disease (Moorthy et al., 1995; Ozdal et al., 2014;
Read et al., 2001c).
Recurrent anterior segment inflammation and prolonged systemic corticosteroid therapy
948
are considered as another risk factor for complicated cataract, which is the most common
949
complication. According to previous studies, cataract occurs in 10.5% to 42% of eyes (Chi et al.,
950
2007; Moorthy et al., 1995; Moorthy et al., 1994; Ohno et al., 1988; Ozdal et al., 2014; Read et al., 32
ACCEPTED MANUSCRIPT
2001c). Read et al (Read et al., 2001c) proposed that the great difference in the rate of cataract
952
may come from the definition of cataract employed among studies, because there was no
953
description of the type of cataract in these studies except their own studies (Moorthy et al., 1994;
954
Read et al., 2001c). We speculate that the proportion of patients which are at different stages
955
may also influence the rate of complicated cataract within a study. The series including more
956
patients at the chronic recurrent stage will thus have a higher rate of complicated cataract. The
957
rate of cataract in VKH children ranges from 23.9% to 61.5% (Abu El-Asrar et al., 2008; Rathinam
958
et al., 1998; Soheilian et al., 2006; Tabbara et al., 1998).
SC
959
RI PT
951
Glaucoma develops in 6% to 45% of eyes (Nakao et al., 2009). The incidence of glaucoma in VKH children is similar to that in the whole population of VKH patients, ranging from 22% to 46%
961
(Rathinam et al., 1998; Tabbara et al., 1998). Forster et al (Forster et al., 1993) analyzed 16
962
patients with VKH disease accompanied by complicated glaucoma and found that nine (56.3%)
963
had open-angle glaucoma and seven (43.7%) had angle-closure secondary to pupillary block.
964
M AN U
960
Subretinal fibrosis and choroidal neovascularization are the complications leading to severe vision loss. Lertsumitkul et al (Lertsumitkul et al., 1999) reported that subretinal fibrosis
966
developed in 40% of 75 patients and choroidal neovascularization in 14.7% of cases. Our results
967
in a Chinese population showed that less than 2% of all 819 eyes investigated were complicated
968
by subretinal fibrosis (Yang et al., 2007). A recent analysis for clinical characteristics in Turkish
969
VKH patients also demonstrated a lower rate of 2% for subretinal fibrosis (Ozdal et al., 2014).
970
Therefore, there is a difference in the rate of subretinal fibrosis depending on the ethnicity. In
971
addition, long standing and recurrence of inflammation are also considered as a risk factor
972
associated with subretinal fibrosis and neovascularization (Chi et al., 2007; Kuo et al., 2000).
974 975 976
EP
AC C
973
TE D
965
Patients who had a disease duration of ≥12 months at presentation were more likely to have
subretinal neovascularization or fibrosis than patients with a disease duration of ＜12 months at the time of presentation (Bykhovskaya et al., 2005; Kuo et al., 2000). In children with VKH disease,
the incidence of subretinal neovascular membranes has been reported to be as high as 54% to 70%
977
(Soheilian et al., 2006; Tabbara et al., 1998). These findings are much higher as compared to a
978
recent study whereby subretinal neovascular membranes occurred in 4.3% and subretinal fibrosis
979
occurred in 2.2% of 46 eyes of children with VKH (Abu El-Asrar et al., 2008).
980
Other complications such as cystoid macular edema (Bykhovskaya et al., 2005; Rutzen et 33
ACCEPTED MANUSCRIPT
al., 1995), band-shaped keratopathy (Yang and Sun, 2011), and visual field defects have also been
982
reported (Nakao et al., 2012; Nakao et al., 2009).
983
Ancillary tests
984
Fluorescein angiography (FA)
985
RI PT
981
FA is a helpful ancillary test for VKH disease and it has been described extensively (da Silva et al., 2009a; Moorthy et al., 1995; Rajendram et al., 2005). Briefly, in the acute stage of VKH
987
disease, FA (Fig 4) reveals numerous punctate hyperfluorescent dots at the level of the RPE. In
988
the late phase of the angiogram, staining of the subretina surrounding the hyperfluorescent dots
989
and pooling of the dye in areas of an exudative retinal detachment are noted. Optic disc
990
hyperfluorescence and leakage can also be seen frequently. Window defects caused by atrophic
991
chorioretinal scars in the late phase of the angiogram are always located in the midperipheral
992
area, which is common in VKH disease and rarely observed in other uveitis entities except for
993
sympathetic ophthalmia. FA during the late stage of VKH reveals nonspecific window defects and
994
blockade due to retinal pigment epithelium damages. FA is also helpful for identifying choroidal
995
neovascularization and subretinal fibrosis.
996
Ultrasonography
TE D
M AN U
SC
986
As a noninvasive ancillary test, B-scan ultrasonography is useful for the diagnosis of VKH
998
disease in the acute stage (Forster et al., 1990). The echographic manifestations of VKH disease
999
include diffuse, low-to-medium reflective thickening of the posterior choroid; serous
1001 1002 1003 1004
detachments of the retina located in the posterior pole or inferiorly; some vitreous opacities with
AC C
1000
EP
997
no posterior vitreous detachment; and posterior thickening of the sclera or episclera. Recently,
high-resolution ultrasonography (20-MHz) has been shown to be helpful in detecting subclinical
ERD and in monitoring response to treatment (Khairallah et al., 2007b). Though the echographic
features of VKH disease are distinct in the context with the history and other physical findings, it
1005
is important to differentiate it from posterior scleritis, benign reactive lymphoid hyperplasia of
1006
the uvea and malignant choroidal melanoma (Moorthy et al., 1995).
1007
Lumbar puncture
1008
According to Sugiura’s diagnostic criteria, lumbar puncture for examining the pleocytosis is 34
ACCEPTED MANUSCRIPT
required, because pleocytosis was found in 80% of patients within 1 week and in 97% of patients
1010
within 3 weeks of the onset of inflammation (Sugiura, 1976a, 1978). A recent study has
1011
demonstrated that more than 70% of acute and chronic VKH patients had pleocytosis in Japan
1012
(Yamaki et al., 2005). Clinically, this procedure is rarely used due to its invasive nature. Analysis of
1013
T lymphocyte subpopulations (CD3+, CD4+ and CD4+ CD45RO+) showed that the profiles were
1014
identical for CSF and aqueous humor but that they differed from the cells found in blood,
1015
suggesting that analysis of CSF may reflect the local immunological reaction at sites (uvea and
1016
meninges) affected by the disease (Kitaichi et al., 2007).
1017
Indocyanine green angiography (ICGA)
SC
RI PT
1009
ICGA has been shown to be one of the most useful tests to observe the evolution of
1019
choroidal inflammatory involvement and to monitor the efficacy of treatments (Bouchenaki and
1020
Herbort, 2001). A set of ICGA signs in VKH disease has been systemically reviewed for the
1021
follow-up of the choroidal inflammation (Bouchenaki and Herbort, 2001; Herbort et al., 2007)
1022
(Fig 4). Early choroidal perfusion in homogeneity has been considered as an important and
1023
specific sign in VKH disease, although there are some controversies (Miyanaga et al., 2010). Early
1024
hyperfluorescent stromal vessels (Fig 4), which indicate severe choroidal stromal inflammatory
1025
vasculopathy, may be used as a semiquantitative parameter by counting the number of these
1026
vessels. Hypofluorescent dark dots, which are thought to correspond to choroidal granulomas,
1027
are the most readily recordable angiographic sign. Other signs include fuzzy or lost vascular
1028
patterns of large stromal vessels seen in the intermediate to late angiographic phases and disc
1029
hyperfluorescence, which indicates very severe disease. Diffuse late choroidal
1030
hyperfluorescenceis also a consistent sign seen by ICGA in VKH. It has been shown that ICGA can
1032 1033
TE D
EP
AC C
1031
M AN U
1018
be used to detect subclinical inflammation in the choroid which cannot be found clinically in early stages or after systemic therapy (Kawaguchi et al., 2010). ICGA signs such as dark dots, fuzzy or
lost vascular and diffuse choroidal hyperfluorescence may indicate choroidal inflammation
1034
(Bouchenaki and Herbort, 2011; Herbort et al., 2007).
1035
Optical coherence tomography (OCT)
1036 1037
OCT has been widely used for evaluating the ERD present in the early stage of VKH disease. With the increase of resolution, OCT reveals more details of ERD and helps to formulate a new 35
ACCEPTED MANUSCRIPT
hypothesis concerning the cause of ERD (Fig 3). Studies have demonstrated two patterns of
1039
serous retinal detachment: true serous retinal detachment and intraretinal fluid accumulation
1040
(Ishihara et al., 2009; Lee et al., 2009). Subretinal septa, which divide the subretinal space of ERD
1041
into several compartments, may represent fibrin membranes resulting from the inflammatory
1042
reaction. These septa may be responsible for multilobular dye pooling revealed by FA (Yamaguchi
1043
et al., 2007). OCT has also been used to study the choroidal folds, folds of RPE, Bruch’s
1044
membrane, and external limiting membrane in VKH disease (Gupta et al., 2009; Hashida et al.,
1045
2014; Mili-Boussen et al., 2013; Sakata et al., 2014; Tsuboi et al., 2015; Vasconcelos-Santos et al.,
1046
2010; Wu et al., 2007; Zhao et al., 2009). Most recently, enhanced depth imaging optical
1047
coherence tomography (EDI-OCT) has been introduced to evaluate the thickness of the choroid
1048
and retina in VKH (Hashizume et al., 2014; Invernizzi et al., 2015; Margolis and Spaide, 2009; Park
1049
et al., 2013; Tagawa et al., 2015; Takahashi et al., 2014). Studies showed that the choroidal
1050
thickness was markedly increased in the acute phase of VKH disease and decreased quickly after
1051
systemic corticosteroid treatment or in the convalescent stage of VKH disease. Obviously, OCT is
1052
becoming a useful tool for evaluating the severity of VKH disease and to monitor the response to
1053
treatment.
1054
Other ancillary tests
SC
M AN U
TE D
1055
RI PT
1038
Ultrasound biomicroscopy (UBM) is helpful to evaluate changes in the anterior segment during VKH disease. Usually, no substantial changes can be detected by UBM in the posterior
1057
uveitis stage and in the remission stage (Wada et al., 2002). During the anterior uveal
1058
involvement stage and the recurrent granulomatous uveitis stage, a shallow anterior chamber,
1059
ciliochoroidal detachment, thickened and swollen ciliary body, anterior rotation and anterior
1061 1062
AC C
1060
EP
1056
bowing of the iris may be visualized by UBM (Gohdo and Tsukahara, 1996; Yang et al., 2007).
Laser flare photometry (LFCM) has been designed to provide an objective measurement for the evaluation of aqueous flare and cells. With the use of LFCM we have been able to show that
1063
recurrent VKH patients displayed a more striking and long-lasting breakdown of the blood–
1064
aqueous barrier and more severe inflammation than initial-onset VKH patients (Fang et al., 2008).
1065
Electroretinography has also been used to evaluate the macular and retinal function in VKH
1066
patients (da Silva et al., 2009b; Yang et al., 2008). Our recent studies have shown a severe 36
ACCEPTED MANUSCRIPT
decrease in visual acuity and diffuse mfERG abnormalities in patients with VKH disease before
1068
treatment, suggesting severe damage of the macular area. The parameters of mfERG (N1 and P1
1069
waves) gradually improved following treatment, indicating that mfERG may be a useful tool to
1070
monitor therapy in patients with VKH disease (Yang et al., 2008). Autofluorescence, magnetic
1071
resonance imaging and other ancillary tests can also be helpful for diagnosis and follow-up of the
1072
disease (Johnston and Teitelbaum, 1990; Koizumi et al., 2010; Vasconcelos-Santos et al., 2010)
1073
(Fig 3). Multi-spectral image (MSI) is a novel non-invasive tool for revealing the morphological
1074
changes of the fundus. Our recent investigation showed a significant higher percentage of
1075
morphological alternations (depigmentation, migration and clumping of pigment, macular
1076
depigmentation and/or hyperpigmentation) discovered by MSI as compared with those detected
1077
by FFA, OCT and FP (manuscript in preparation).
1078
Therapy
SC
M AN U
1079
RI PT
1067
Rapid and aggressive therapy using systemic corticosteroids should be installed once the diagnosis is made. The majority of VKH patients in the acute stage respond to the treatment with
1081
corticosteroids and gradually tapered systemic corticosteroids should be maintained for several
1082
months to prevent progression into the chronic stage and to prevent future recurrences.
1083
Accumulating evidence has suggested that prescription of immunosuppressive agents at the
1084
acute stage of VKH disease is associated with better visual outcomes (Abu El-Asrar et al., 2013;
1085
Urzua et al., 2015). For patients at the chronic stage, immunosuppressive agents are required to
1086
control the inflammation. Recently developed biologic agents have been shown to be effective
1087
for refractory VKH disease and for treating neovascularization occurring in the chronic stage
1088
(Busanyova et al., 2013; Cordero-Coma et al., 2013; Wu et al., 2009; Zmuda et al., 2013). Topical
1090 1091
1092 1093
EP
AC C
1089
TE D
1080
steroids, cycloplegics and mydriatics are recommended to control the associated anterior uveitis (Moorthy et al., 1995). Possible side-effects of all medications should be closely monitored during follow-up.
Corticosteroids Early and aggressive systemic corticosteroids are still the mainstay of treatment for acute
1094
VKH disease (Lai et al., 2009; Moorthy et al., 1995; Read et al., 2006; Rubsamen and Gass, 1991).
1095
The average initial dose of corticosteroids is 80 to 100 mg of oral prednisone per day and 37
ACCEPTED MANUSCRIPT
maintained for 2-4 weeks, although a dose of more than 200 mg has been recommended for
1097
severe cases (Hayasaka et al., 1982; Moorthy et al., 1995; Rubsamen and Gass, 1991). The initial
1098
high dose of corticosteroids can be administered either orally or intravenously. Some
1099
investigators reported that the initial treatment with pulsed high dose intravenous
1100
corticosteroids rapidly improved serous detachment (Sasamoto et al., 1990; Yamanaka et al.,
1101
2002).The effect of two routes of administration of corticosteroids (orally or intravenously
1102
followed by an oral taper) have been compared on the outcome of VKH disease and showed no
1103
difference concerning the long-term visual acuity recovery and ocular complications between the
1104
two groups(Read et al., 2006). Therefore, oral administration may be the first choice, except for
1105
severe cases. Following the initial high dose, systemic corticosteroid treatment should be tapered
1106
off gradually, usually maintaining treatment for at least 6 months (Lai et al., 2009; Moorthy et al.,
1107
1995; Read et al., 2006), although a longer duration of 45 months has also been reported (Fujioka
1108
et al., 1980). Patients who received systemic corticosteroid treatment for less than 6 months have
1109
been demonstrated to be more likely to have a recurrence and more severe vision loss than those
1110
who received treatment for more than 6 months (Lai et al., 2009). As for the tapering course,
1111
there is still no standard dosage. A study comparing the effect of high- or medium-dose systemic
1112
corticosteroid treatment during the early 4-month treatment phase demonstrated that a dose of
1113
0.36 mg/kg/day is not sufficient to suppress subclinical progression whereas a dose as high as
1114
0.75 mg/kg/day was required to control the disease (Kawaguchi et al., 2010). For patients who
1115
cannot tolerate systemic corticosteroids, triamcinolone acetonide and dexamethasone
1116
intravitreal implants have been shown to improve visual acuity and serous retinal detachment
1117
and may thus be an alternative tool in the treatment (Andrade et al., 2004; Burkholder et al.,
1119 1120 1121
SC
M AN U
TE D
EP
AC C
1118
RI PT
1096
2015; Cao et al., 2014; Karacorlu et al., 2006; Latronico et al., 2015; Zarranz-Ventura et al., 2014). In our clinic, VKH patients are treated with oral corticosteroids (initial dosage, 1.0 –1.2
mg/kg per day), often in combination with immunosuppressive agents (see below) (Yang et al., 2007). The corticosteroids dosage is tapered gradually and treatment is continued for at least 10
1122
months. Corticosteroid eye drops and cycloplegic agents are used for cases with anterior
1123
chamber reaction. Local treatment with eye drops is usually continued for 2 to 4 weeks.
1124
Prolonged corticosteroid eye drops are given to chronic or refractory VKH patients, or patients
1125
with macular edema (ME). Intravitreal triamcinolone (IVTA), according to our experience, reduces 38
ACCEPTED MANUSCRIPT
1126
ME and improves vision, but cataract and glaucoma are frequent complications. Corticosteroid
1127
implants are currently not commercially available in China.
1128
Immunosuppressive agents For those patients presenting at the chronic phase or with chronic recurrent disease, and
RI PT
1129
who are intolerant or resistant to corticosteroids, immunosuppressive agents (such as
1131
cyclosporine, azathioprine, methotrexate, chlorambucil and cyclophosphamide) are employed to
1132
suppress the ocular inflammation (Andreoli and Foster, 2006; Rao, 2006; Yang et al., 2007). One
1133
of the most extensive studies on the use of immunosuppressive agents described the use of
1134
cyclosporine A (CsA) in the treatment of VKH (Nussenblatt et al., 1985; Vitale et al., 1996;
1135
Wakefield et al., 1990). Later studies compared the efficacy of azathioprine and cyclosporine for
1136
VKH disease in combination with corticosteroids and showed that CsA seems to be a better
1137
glucocorticoid-sparing agent than azathioprine (Cuchacovich et al., 2010). Our own in vitro
1138
studies showed an inhibitory effect of CsA and corticosteroids on the production of IFN-γ and
1139
IL-17 by T cells obtained from patients with VKH disease (Liu et al., 2009). Either dexamethasone
1140
or prednisone do not completely inhibit the production of IL-17 and IFN-γ. However, low doses of
1141
CsA (3–5 mg/kg per day) in combination with low doses of corticosteroids can decrease IL-17 and
1142
IFN-γ more effectively (Liu et al., 2009). These results may partially explain the effect of CsA for
1143
treatment of VKH disease. Azathioprine, an inhibitor of purine synthesis, has also been shown to
1144
be effective for the treatment of VKH disease, usually in combination with corticosteroids
1145
(Cuchacovich et al., 2010; Kim and Yu, 2007; Pacheco et al., 2008). Aggressive triple
1146
immunosuppressive agent therapy (oral prednisolone, azathioprine and cyclosporine) has been
1148 1149 1150 1151
M AN U
TE D
EP
AC C
1147
SC
1130
reported for the treatment of VKH disease and resulted in a rapid remission in all patients and
helped in preventing recurrences (Agarwal et al., 2006). Taken together, the use of these additional immunosuppressive agents has proven to be a great complement for corticosteroids in controlling the inflammation in VKH disease. The discussion nowadays among uveitis specialists is whether immunosuppressive agents
1152
should be employed as a first-line therapy for VKH disease. Paredes et al (Paredes et al., 2006)
1153
reported the results of a series of 8 patients with VKH disease who received prompt
1154
immunosuppressive agents with or without systemic corticosteroids and compared their 39
ACCEPTED MANUSCRIPT
treatment outcomes with those of another group of 5 patients treated with prolonged steroid
1156
therapy with or without the delayed addition of immunosuppressive agents. They concluded that
1157
patients treated initially with immunosuppressive agents had a better visual outcome than those
1158
who received a prolonged treatment with corticosteroids. Other recent studies confirmed the
1159
benefit of first-line immunomodulatory therapy for improving visual acuity and controlling
1160
inflammation (Abu El-Asrar et al., 2013; Urzua et al., 2015). Our data also indicate that first-line
1161
immunomodulatory therapy is associated with the better visual outcome and a lower frequency
1162
of recurrence (not published). The studies described above are uncontrolled and prospective
1163
randomized clinical trials are needed to validate the various treatment options for VKH (Rao,
1164
2006).
SC
In our clinic, systemic corticosteroid treatment is combined with Cyclosporine or
M AN U
1165
RI PT
1155
chlorambucil in those patients who had severe exudative retinal detachment (Yang et al., 2007).
1167
Treatment is often continued for one year. The initial dosage of cyclosporine is 3 to 5 mg/kg per
1168
day and chlorambucil is usually used at 0.1 mg/kg per day. The dosages of corticosteroids and
1169
other immunosuppressive agents were adjusted according to severity of the uveitis or in case of
1170
the occurrence of side effects. White blood cell counts, kidney and liver functions were regularly
1171
monitored.
1172
Biologic agents
Infliximab, a chimeric (mouse–human) immunoglobulin monoclonal antibody to tumor
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necrosis factor alpha (Fig 5), has been shown to be effective in the treatment of uveitis, especially
1175
refractory recurrent or corticosteroid-resistant uveitis (Cordero-Coma et al., 2013; Zmuda et al.,
1176 1177 1178 1179
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2013). It can bind both soluble and membrane bound TNF-α, neutralizing the biologic activity of TNF-α which has been implicated in the pathogenesis of uveitis (Santos Lacomba et al., 2001). Several case reports describing the treatment of VKH disease with infliximab have been reported
(Table 7) (Chen et al., 2008; Kahn et al., 2006; Khalifa et al., 2010; Niccoli et al., 2009; Suhler et al.,
1180
2009; Zmuda et al., 2013). The efficacy of Infliximab for VKH disease seems promising, especially
1181
for refractory recurrent or corticosteroid-resistant uveitis.
1182 1183
Interferon α2a (IFN-α2a), an agent that has both immunomodulatory and antiviral properties, has been successfully used in the treatment of severe and refractory uveitis 40
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associated with Behcet’s disease (Touitou et al., 2007). However, care should be taken when
1185
employing IFN-α2a for the treatment of VKH disease, in view of the observation of
1186
interferon-induced VKH-like disease in patients treated with this drug for chronic viral hepatitis C
1187
(Al-Muammar et al., 2010; Papastathopoulos et al., 2006; Soma et al., 2011). Touitou et al
1188
(Touitou et al., 2007) believe that it is still a good option for VKH patients without HCV infection
1189
because of the observed spectacular efficacy of IFN-α2a treatment (Touitou et al., 2007). As yet,
1190
these findings have not been confirmed by others.
Two other biologic agents known for controlling inflammation have also been reported for
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1191
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1184
the treatment of refractory uveitis. Adalimumab, a biologic agent targeting TNF (Fig 5), was also
1193
reported to be effective for the treatment of VKH disease in a patient with refractory recurrent
1194
uveitis (Diaz Llopis et al., 2007; Jeroudi et al., 2014). Rituximab, a human–murine chimeric
1195
monoclonal antibody targeting CD20 (Fig 5), has also been reported to be effective in patients
1196
with VKH disease unresponsive to TNF blockers (Dolz-Marco et al., 2011; Umran and Shukur,
1197
2015).
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Anti-VEGF agents have been widely used to control ocular neovascularization and macular
1199
edema (Rodrigues et al., 2009). Bevacizumab, an anti-VEGF agent (Fig 5), has been reported to be
1200
effective for controlling neovascular membrane formation and improving visual acuity (Raffa and
1201
Bawazeer, 2009; Wu et al., 2009). Arevalo et al (Arevalo et al., 2011) examined 22 consecutive
1202
patients with inflammatory choroidal neovascularization which were treated with intravitreal
1203
bevacizumab (1.25 or 2.5mg) after the underlying uveitic condition was controlled and found that
1204
intravitreal bevacizumab provided stability or improvement in best-corrected visual acuity at 24
1205
months. A retrospective multicenter study including 81 patients confirmed efficacy of
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bevacizumab for inflammatory ocular neovascularization refractory to standard therapy (Mansour et al., 2012). Combination therapy of intravitreal injection of bevacizumab and
triamcinolone acetate for recurrent inflammatory choroidal neovascularization has also been reported recently (Pai et al., 2012; Reibaldi et al., 2014).The studies mentioned above did not
1210
include VKH patients. A novel anti VEGF drug, conbercept (Fig 5), that has been approved by the
1211
China Food and Drug Administration for the treatment of neovascular AMD in China was recently
1212
used in our clinic to treat macular edema and choroidal neovascularization in patients with VKH
1213
disease. Our results demonstrated that anti-VEGF therapy had a significant effect in controlling 41
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1214
the edema and choroidal neovascularization and improving BCVA (unpublished data).
1215
Management of VKH in special groups
1216
In children, the mainstay treatment for acute VKH disease is high-dose corticosteroids. Considering the side effects of prolonged systemic corticosteroid therapy, especially growth
1218
retardation, successful treatment of children with VKH disease with immunosuppressive agents
1219
such as methotrexate, cyclosporine, azathioprine and cyclophosphamide has recently been
1220
reported (Abu El-Asrar et al., 2008; Martin et al., 2010; Soheilian et al., 2006; Tabbara et al.,
1221
1998). Biologic agents have also been reported in the treatment of children with VKH and
1222
showed significant therapeutic effectiveness (Jeroudi et al., 2014; Umran and Shukur, 2015).
1223
These reports are mainly based on retrospective studies and case reports and to date no
1224
randomized clinical trials have been published. There is still no standard regimen for these
1225
immunosuppressive agents in the treatment for pediatric VKH disease, because VKH is a
1226
relatively rare cause of uveitis in children. It should be noted that collaboration with a
1227
pediatrician is critical when high-dose corticosteroids and/or immunosuppressive agents are
1228
prescribed.
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High-dose corticosteroids have also been reported to be effective for VKH disease during
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pregnancy. These patients who had healthy deliveries received a treatment of high-dose
1231
corticosteroids in the second and third trimesters of pregnancy (Friedman et al., 1980; Miyata et
1232
al., 2001; Tien and Teoh, 2009). However, spontaneous abortions and a lower birth-weight have
1233
been reported (Doi et al., 2000; Steahly, 1990), although the relationship between these events
1234
and corticosteroid therapy was not established.
1236 1237
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Management of complications Ocular complications usually require additional management beyond systemic therapy.
Cataract surgery should be performed 3 months after complete resolution of inflammation
1238
(Moorthy et al., 1994). Steroid prophylaxis from 4 days to 2 weeks before and after surgery is
1239
necessary (Ganesh et al., 2004; Meacock et al., 2004; Quek et al., 2011). Ganesh et al (Ganesh et
1240
al., 2004) observed a lower incidence of synechiae and posterior capsule opacification in patients
1241
receiving phacoemulsification when compared to those who received extra-capsular cataract 42
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extraction, suggesting the advantages of phacoemulsification over extra-capsular cataract
1243
extraction in complicated cataract. These advantages may partially result from the fact that the
1244
blood-aqueous barrier is less affected following phacoemulsification and surface-modified
1245
intraocular lens implantation. However, Quek et al (Quek et al., 2011) failed to find a difference in
1246
outcome between VKH eyes that underwent extracapsular cataract extraction by manual nuclear
1247
expression and eyes that underwent phacoemulsification. Posterior segment complications are
1248
the main determinants for postoperative visual acuity in VKH (Ganesh et al., 2004; Quek et al.,
1249
2011). If cystoid macular edema occurs, supplemental treatment with topical non-steroidal
1250
anti-inflammatory drugs should be considered (Quek et al., 2011).
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Different strategies should be considered for glaucoma caused by VKH disease, because several mechanisms including blocking the trabecular meshwork by inflammatory cells, damage
1253
of the trabecular meshwork, peripheral anterior synechiae, pupillary block due to extensive
1254
posterior synechiae and corticosteroid-induced ocular hypertension may be involved (Forster et
1255
al., 1993; Moorthy et al., 1995; Read et al., 2001c). In addition to medications, surgical
1256
intervention including laser iridotomy, surgical iridectomy, trabeculectomy and Molteno
1257
implantation have been used to treat glaucoma in this patient group (Bykhovskaya et al., 2005;
1258
Forster et al., 1993). It should be noted that a subgroup of VKH disease presenting with a bilateral
1259
increased IOP responds well to corticosteroids but not to anti-glaucoma treatment (Yang et al.,
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2011).
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The risk of subretinal neovascularization or fibrosis can be reduced by 82% with oral
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corticosteroid treatment (Bykhovskaya et al., 2005). In addition to the anti-VEGF therapy, laser
1263
photocoagulation (Wu et al., 2009), photodynamic therapy with verteporfin (Farah et al., 2002;
1264 1265 1266 1267
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Nowilaty and Bouhaimed, 2006), and surgical excision (Foster et al., 2000) have also been reported for the treatment of subretinal fibrosis.
Prognosis
The visual prognosis of VKH disease is generally good in case of prompt diagnosis and
1268
appropriate treatment with corticosteroids and immunosuppressive agents (Damico et al., 2005b;
1269
Moorthy et al., 1995; Rajendram et al., 2005; Read et al., 2001b; Yang et al., 2007). Ozdal et al
1270
(Ozdal et al., 2014) reported that 73.4% of 32 Turkish VKH patients (10 complete, 16 incomplete,
1271
6 probable; 16 at acute stage, 16 at chronic stage) achieved BCVA ≥20/40. In 67 (134 eyes) 43
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Singapore VKH patients, about 74% achieved BCVA ≥20/40 (Chee et al., 2009). In 87 (174 eyes )
1273
Saudi Arabia VKH patients, including 53 patients with initial-onset acute VKH disease and 34
1274
patients with chronic recurrent VKH disease, about 76% achieved BCVA ≥20/40 (Abu El-Asrar et
1275
al., 2013). After one year treatment, 61 eyes (67.77%) of South Indian VKH patients (n=45; 90
1276
eyes, 23 patients presented in the acute phase) achieved BCVA of ≥ 20/40 (Murthy et al., 2007).
1277
Mondkar et al reported that only 15.4% of 87 consecutive Indian VKH cases (48 cases were seen
1278
within 3 months of onset of symptoms) retained a BCVA of 6/18 or better (Mondkar et al., 2000).
1279
A large cohort study including of 410 consecutive Chinese VKH patients showed that, with the
1280
treatment of corticosteroids alone or combined with other immunosuppressive agents, all the 73
1281
patients (146 eyes) referred to our clinical within 2 months after onset achieved a visual acuity of
1282
20/20 (Yang et al., 2007). For 337 patients (673 eyes) with recurrent ocular inflammation which
1283
were referred to our clinic 2 months after onset and were initially treated in other hospitals, up
1284
to 62.5% achieved a vision ≥20/40 (Yang et al., 2007). Most studies mentioned above show a
1285
good response to treatment suggesting that ethnicity or region does not affect the outcome. The
1286
only study mentioning a poor response might be due to problems concerning the access of
1287
appropriate medication (Mondkar et al., 2000).
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Initial visual acuity at presentation has been shown to be significantly associated with final visual acuity (Al-Kharashi et al., 2007; Ohno et al., 1988; Read et al., 2001a; Read et al., 2001b).
1290
Furthermore, recent studies showed that a good visual acuity at one month after starting
1291
treatment predicted a good prognosis (Chee et al., 2009). Prompt administration of
1292
corticosteroids and slowly tapering them off is critical for the good prognosis of acute VKH
1293
disease (Read et al., 2001b). However, more than half of these patients may develop chronic
1295 1296 1297
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disease with consequent poor visual prognosis due to delayed treatment (later than 15 days from disease onset) and inadequate treatment (suboptimal dose and time of maintaining treatment)
(Chee et al., 2007; Kawaguchi et al., 2010; Lai et al., 2009), though different oral corticosteroid regimens have been explored. Cataract, glaucoma, subretinal fibrosis, choroidal
1298
neovascularization, or choroidal atrophy are the main complications associated with a poor
1299
prognosis (Chee et al., 2007; Kawaguchi et al., 2010; Lai et al., 2009; Yang et al., 2007). Patients
1300
treated initially with immunosuppressive agents had a better visual outcome than those who
1301
received a prolonged treatment with corticosteroids alone (Paredes et al., 2006). Other studies 44
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and our data also confirmed the benefit of first-line immunomodulatory therapy for improving
1303
visual acuity and controlling inflammation (Abu El-Asrar et al., 2013; Paredes et al., 2006; Urzua
1304
et al., 2015). In addition, triple-agent therapy, including corticosteroids, azathioprine, and
1305
cyclosporine, was associated with a rapid remission in a series of severe recalcitrant VKH cases
1306
(Agarwal et al., 2006).
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Literature reports concerning the role of age at disease onset and prognosis of visual
1308
acuity show conflicting data. Some studies showed a poor prognosis with older age at VKH onset
1309
(Chee et al., 2009; Read et al., 2001b) whereas others reported a worse prognosis in young
1310
patients (Ohno et al., 1988; Tabbara et al., 1998). The visual prognosis of child VKH disease seems
1311
to be quite variable depending on the time interval between onset of the disease and treatment
1312
(Abu El-Asrar et al., 2008; Rathinam et al., 1998; Tabbara et al., 1998). Pregnancy showed a
1313
beneficial effect on disease activity (Wang and Chan, 2014). Ocular inflammation usually
1314
improved during pregnancy and rebounded after delivery (Chiam et al., 2013; Friedman et al.,
1315
1980; Kump et al., 2006; Nohara et al., 1995; Rabiah and Vitale, 2003; Snyder and Tessler, 1980;
1316
Steahly, 1990), though in some cases disease did not recur after delivery (Friedman et al., 1980).
1317
Future directions
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VKH disease, a bilateral uveitis frequently associated with manifestations of the skin,
1319
auditory system and meninges, is common in certain ethnic populations with a susceptible
1320
genetic background. In addition to HLA antigens, several other genetic susceptibility factors have
1321
been identified and most of the factors identified so far are involved in the common pathways of
1322
autoimmune disease. Although various VKH disease specific predisposing genetic factors have
1323
been identified, it is expected that many more will be identified in the near future. .The exact role
1325 1326 1327
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of these predisposing factors and how their genetic basis causes the development of VKH disease needs further investigation. A complex network, including T cells, cytokines, chemokines, and transcription factors are
instrumental in keeping the balance between tolerance and autoimmunity against melanocyte
1328
associated antigens. Disturbance of this homeostatic balance is considered as the initial event in
1329
the pathogenesis of VKH disease. The steps leading to the disturbance of immune homeostasis
1330
are far from clear however. Environmental factors such as the microbiome are currently
1331
considered as possible precipitating factors in the development of ocular inflammatory disease. 45
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Novel techniques examining the composition of the microbiome in VKH patients may elucidate
1333
whether the microbial flora plays a role in the initiation or recurrence of this disease, how the
1334
microbiome interacts with predisposing genetic factors and its effects on autoimmunity and
1335
inflammation and whether this knowledge can be integrated in its treatment.
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1332
The diagnosis of VKH disease is mostly based on clinical manifestations. Therefore, it is
1337
extremely important to be familiar with the evolutionary progress of the disease, because the
1338
clinical features at the different stages vary greatly. Further identification of biomarkers is needed
1339
to unravel disease mechanisms and to investigate whether they can be used to follow disease
1340
progress and its response to therapy.
1341
SC
1336
High-dose corticosteroids are still the mainstay of therapy for VKH disease. However, mounting evidence for the efficacy of immunosuppressive agents and biologic agents is being
1343
reported. Is it necessary to employ immunosuppressive agents and biologic agents as the first
1344
line therapy? How to determine the duration and dosage of immunosuppressive agents for
1345
patients? How to maximize the role of the newly developed ancillary tests for diagnosis,
1346
follow-up and evaluating the efficacy of therapies? Multi-centered, prospective, randomized
1347
studies are urgently needed.
1348
Acknowledgments
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This work was supported by Natural Science Foundation Project (81470620), Natural Science Foundation Major International (Regional) Joint Research Project (81320108009), Key
1351
Project of Natural Science Foundation (81130019), National Natural Science Foundation Project
1352
(31370893), Basic Research program of Chongqing (cstc2013jcyjC10001), Chongqing Key
1353
Laboratory of Ophthalmology (CSTC, 2008CA5003), National Key Clinical Specialties Construction
1355 1356 1357 1358
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Program of China, Key Project of Health Bureau of Chongqing (2012-1-003), Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002), National Natural Science Foundation Project of CQ (cstc2013jcyjA10015), and Fund for PAR-EU Scholars Program.
Competing financial interests The authors declare no competing financial interests.
1359
Figure legends
1360 1361
Fig 1. Schematic hypothesis for the pathogenesis of VKH disease: A, Two factors are involved in the initial stage of VKH disease, genetic factors and environmental triggers. Disease specific risk 46
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1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404
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factors such as HLA-DR4 and a number of other common “immune response” gene polymorphisms have been identified in VKH disease. These factors together determine the start of VKH disease. Virus is widely accepted as the triggering factor. However, permissive risk alleles and timing of triggering need further analysis. At the proper timing, dendritic cells and other innate immune cells meet pathogen-associated molecular pattern (PAMP) in the susceptible individuals. B, On the one hand, antigen presenting cells (APCs) become mature and present the PAMP to naïve T cells. Under the specific immune conditions of the individual, APCs secrete a certain profile of cytokines. This specific profile of cytokines determines the direction of differentiation of naïve T cells: Th1, Th17, Th2 or Tregs. In VKH disease, the overwhelming differentiation of T cells has been demonstrated to be shifted towards a population of Th1 and Th17 cells. C, Cytokines, chemokines and other factors secreted by Th1, Th17, Th2 and other types of immune competent cells constitute a specific immune environment in the susceptible individual. This immune environment in turn has an effect on the differentiation of naïve T cells directly or indirectly, forming a complicated network of immune response. D, The immune environment allows activation of effector T cells and other effector immune cells to attack tissue with pigment including the choroid, ear, skin and meninges. Selection of the target tissues in VKH disease may be due to the similarity between viral antigens and proteins from pigmented cells (molecular mimicry theory). Fig 2. Genes tested for susceptibility to VKH disease: The underlined bold genes have been shown to be associated with VKH disease.
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Fig 3. Fundus photography, autofluorescence and OCT examination of a patients with acute VKH disease. Multiple exudative retinal detachment (ERD), optic disc swelling and optic disk hyperemia were found in both eye.
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Fig 4. FFA and ICG of the same patient in Fig 3. Numbers of punctate hyperfluorescent dots are seen in the early stage of FFA. In the late phase of FFA, pooling of the dye in areas of an exudative retinal detachment, optic disc hyperfluorescence and leakage are noted. Early choroidal perfusion inhomogeneity and dot hyperfluorescence are noted in ICG. Fig 5. Schematic structure of biologic agents used in VKH disease
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1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393
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Yang, P., Sun, M., 2011. Band-shaped keratopathy in Chinese patients with Vogt-Koyanagi-Harada syndrome. Cornea 30, 1336-1340.
Yang, P., Zhang, Z., Zhou, H., Li, B., Huang, X., Gao, Y., Zhu, L., Ren, Y., Klooster, J., Kijlstra, A., 2005.
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Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res 30, 943-948.
Yang, Y., Xiao, X., Li, F., Du, L., Kijlstra, A., Yang, P., 2012. Increased IL-7 expression in
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Yao, J., Chen, Y., Shao, T., Ling, Z., Wang, W., Qian, S., 2013. Bilateral acute angle closure glaucoma as a presentation of vogt-koyanagi-harada syndrome in four chinese patients: a small case series. Ocul Immunol Inflamm 21, 286-291.
Ye, Z., Wang, C., Tang, J., Zhou, Y., Bai, L., Liu, Y., Kijlstra, A., Yang, P., 2015. Decreased interleukin-37 expression in Vogt-Koyanagi-Harada disease and upregulation following immunosuppressive treatment. J Interferon Cytokine Res 35, 265-272.
Yi, X., Du, L., Hou, S., Li, F., Chen, Y., Kijlstra, A., Yang, P., 2013. FGFR1OP tagSNP but not CCR6 e69358.
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polymorphisms are associated with Vogt-Koyanagi-Harada syndrome in Chinese Han. PLoS One 8, Yi, X., Yang, P., Sun, M., Yang, Y., Li, F., 2011. Decreased 1,25-Dihydroxyvitamin D3 level is involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. Mol Vis 17, 673-679. Yu, H., Liu, Y., Bai, L., Kijlstra, A., Yang, P., 2014. Predisposition to Behcet's disease and VKH syndrome by genetic variants of miR-182. J Mol Med (Berl) 92, 961-967.
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Yuasa, T., Matsumoto, K., Hohki, T., Mimura, Y., 1975. Identification of antibody-producing cells in
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peripheral lymphocytes of Vogt-Koyanagi-Harada's syndrome with immunocyte adherence (rosette-formation) technique. Acta Soc Ophthalmol Jpn 79, 1389-1392. Zarranz-Ventura, J., Carreno, E., Johnston, R.L., Mohammed, Q., Ross, A.H., Barker, C., Fonollosa, A., Artaraz, J., Pelegrin, L., Adan, A., Lee, R.W., Dick, A.D., Sallam, A., 2014. Multicenter study of intravitreal dexamethasone implant in noninfectious uveitis: indications, outcomes, and reinjection frequency. Am J Ophthalmol 158, 1136-1145 e1135. Zhang, M., Qiu, C., Hu, T., 2000. [Association of HLA-DRB genes with Vogt-Koyanagi-Harada syndrome in a Chinese Han population]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 22, 36-40. Zhang, Q., Qi, J., Hou, S., Du, L., Yu, H., Cao, Q., Zhou, Y., Liao, D., Kijlstra, A., Yang, P., 2014. A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis. PLoS One 9, e96943. 66
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Zhao, C., Zhang, M., Wen, X., Dong, F., Han, B., Du, H., 2009. Choroidal folds in acute Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm 17, 282-288. Zhao, M., Jiang, Y., Abrahams, I.W., 1991. Association of HLA antigens with Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Arch Ophthalmol 109, 368-370. Zheng, X., Wang, D., Hou, S., Zhang, C., Lei, B., Xiao, X., Kijlstra, A., Yang, P., 2012. Association of population. Ophthalmology 119, 2514-2518.
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macrophage migration inhibitory factor gene polymorphisms with Behcet's disease in a Han Chinese Zhernakova, A., van Diemen, C.C., Wijmenga, C., 2009. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10, 43-55.
Zhou, Q., Hou, S., Liang, L., Li, X., Tan, X., Wei, L., Lei, B., Kijlstra, A., Yang, P., 2012. MicroRNA-146a and Ets-1 gene polymorphisms in ocular Behcet's disease and Vogt-Koyanagi-Harada syndrome. Ann Rheum Dis.
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sight-threatening corticosteroid-resistant Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm 21,
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Table 1 Criteria proposed by the American Uveitis Society for diagnosis of VKH diseasea 1) Patient should have no history of ocular trauma or surgery; 2) At least three of the following four signs should be present: a) bilateral chronic iridocyclitis;
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b) posterior uveitis, including exudative retinal detachment, formefruste of exudative retinal detachment, disk hyperemia or edema, and "sunset glow" fundus; c) neurologic signs of tinnitus, neck stiffness, cranial nerve or central nervous system problems, or CSF pleocytosis; d) cutaneous findings of alopecia, poliosis, or vitiligo. from Snyder and Tessler, 1980
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Table 2 Diagnostic criteria proposed by Sugiura for VKH disease (Sugiura, 1978) Major symptom 1. Acute bilateral uveitis with simultaneous involvement of both eyes. Symptoms may not be noted for 1–10 days in the second eye. Major symptom 2. Circumscribed retinal edema most markedly at the posterior pole. Fluorescein angiography reveals characteristic leakage of dye through the retinal pigment epithelium into the subretinal spaces.
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Major symptom 3. Pleocytosis of the cerebrospinal fluid is noted in the early stages of the disease. Dysacousia, vertigo, and scalp sensitivity when touching the hair are of value in early diagnosis, if present.
Minor symptom 1. Floating cells in the anterior chamber, granulomatous keratic precipitates, and iris nodules are important signs that may be absent in early stages.
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Minor symptom 2. Hair loss and depigmentation of the eye, skin, and hair are also important signs in the convalescent stage. Depigmentation of the corneal limbus (Sugiura’s sign) appears earliest(Friedman and Deutsch-Sokol, 1981), roughly 1 month after onset, and is also of value for confirming the early diagnosis if present.
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Table 3. Diagnostic Criteria for Vogt-Koyanagi-Harada Disease a Complete Vogt-Koyanagi-Harada disease (criteria 1 to 5 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis 2. No clinical or laboratory evidence suggestive of other ocular disease entities
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3. Bilateral ocular involvement (a or b must be met, depending on the stage of disease when the patient is examined) a. Early manifestations of disease
(1) There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disk hyperemia), which may manifest as one of the following (a) Focal areas of subretinal fluid, or (b) Bullous serous retinal detachments
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(2) With equivocal fundus findings; both of the following must be present as well:
(a) Focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence, pooling within subretinal fluid, and optic nerve staining (listed in order of sequential appearance) by fluorescein angiography, and b. Late manifestations of disease
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(b) Diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography. (1) History suggestive of prior presence of findings from 3a, and either both (2) and (3) below, or multiple signs from (3) (2) Ocular depigmentation (either of the following manifestations is sufficient): (a) Sunset glow fundus, or (b) Sugiura sign (3) Other ocular signs
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(a) Nummular chorioretinal depigmented scars, or (b) Retinal pigment epithelium clumping and/or migration, or (c) Recurrent or chronic anterior uveitis.
4. Neurological/auditory findings (may have resolved by time of examination).
b. Tinnitus, or
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a. Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors; headache alone is not sufficient to meet definition of meningismus, however), or
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c. Cerebrospinal fluid pleocytosis
5. Integumentary finding (not preceding onset of central nervous system or ocular disease) a. Alopecia, or b. Poliosis, or c. Vitiligo
Incomplete Vogt-Koyanagi-Harada disease (criteria 1 to 3 and either 4 or 5 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis, and 2. No clinical or laboratory evidence suggestive of other ocular disease entities, and 3. Bilateral ocular involvement. 4. Neurologic/auditory findings; as defined for complete Vogt-Koyanagi-Harada disease above, or 5. Integumentary findings; as defined for complete Vogt-Koyanagi-Harada disease above Probable Vogt-Koyanagi-Harada disease (isolated ocular disease; criteria 1 to 3 must be present)
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1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis. 2. No clinical or laboratory evidence suggestive of other ocular disease entities. 3. Bilateral ocular involvement as defined for complete Vogt-Koyanagi-Harada disease above. from Am J Ophthalmol2001:131, 647-652.
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Table 4
The ratio of pediatric VKH reported previously
Authors
Total VKH
Pediatric VKH (%)
Regions
97
13 (13.5%)
Riyadh, Saudi Arabia
(Rathinam et al., 1998)
98
3 (3.1%)
Madurai, India
(Martin et al., 2010)
267
22 (8.2%)
Madurai, India
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(Tabbara et al., 1998)
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Table 5
The proportion of male patients with VKH disease as reported previously Cases
Male (%)
Regions
(Ohno et al., 1977)
51
23(45.1%)
North California, USA
(Nussenblatt, 1988)
46
10(21.7%)
USA
(Snyder and Tessler, 1980)
20
8(40.0%)
USA
(Belfort Junior et al., 1988)
33
10 (30.3%)
Brazil
(Sasamoto et al., 1990)
47
29(61.7%)
Sapporo, Japan
(Rubsamen and Gass, 1991)
22
5(22.7%)
Miami, USA
(Beniz et al., 1991)
48
15(31.2%)
South California, USA
(Moorthy et al., 1995)
65
17(26.2%)
Los Angeles, USA
(Tabbara et al., 1998)
97
64(65.9%)
Riyadh, Saudi Arabia
(Kim et al., 2000)
18
7(38.9%)
South Korea
(Mondkar et al., 2000)
87
33(37.9%)
Chennai, India
(Yamaki et al., 2005)
49
19(38.8%)
Akita, Japan
(Chee et al., 2007)
89
37(42.13%)
Singapore
(Khairallah et al., 2007b)
49
17(34.7%)
Tunisia
45
(Yang et al., 2007)
410
(Horie et al., 2009)
167
(Yodmuang et al., 2012)
48
(Llorenc et al., 2015)
19
(Zheng et al., 2015)
199
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(Tugal-Tutkun et al., 2007)
18(37.5%)
South California, USA
13(34.6%)
Turkey
215(52.4%)
China
72(43.1%)
Sapporo or Yokohama, Japan
18(37.5%)
Thailand
3(15%)
Spain
134(67.3%)
China
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Table 6. The information on candidate genes which have been evaluated by different groups Genes
Functions
References
IL-23R
Interleukin-23 receptor, an important element for Th17 mediated responses
(Jiang et al., 2010)
IL-17
Interleukin-17, an important inflammatory factor identified recently
(Shu et al., 2010)
IFN-γ
Interferon gamma
(Horie et al., 2007)
IL-12B, IL-12Rβ1/β2
Interleukin-12 related subunit genes
(Li et al., 2014)
CTLA-4
Cytotoxic T lymphocyte-associated antigen-4, a critical negative regulator of the T cell-mediated immune response
(Du et al., 2008)
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Cytokines and their receptors
Transcription factors and related proteins
Small ubiquitin-like modifier 4, an transcription factor involved in the regulation of NF-кB
(Hou et al., 2008)
PTPN22
Protein tyrosine phosphatase non-receptor 22 gene, an important negative regulator of T cell activation
(Horie et al., 2009; Zhang et al., 2014)
Fc receptor-like 3 gene, an immunoregulatory gene
(Li et al., 2009)
leucine-rich repeat protein 1, a key regulator of the innate immune system
(Horie et al., 2011)
TGFBR3
Type III Transforming growth factor-β, a key factor in regulating and mediating transduction of TGF-β signaling
(Chen et al., 2012b)
Ets-1
Transcription factor Ets-1
(Zhou et al., 2012)
TNFAIP3
Encoding A20 protein, a negative regulator of the NF-KB signaling pathway
(Li et al., 2013)
FGFR10P
A gene region shown to be associated with a variety of
(Yi et al., 2013)
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NLRP1
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autoimmune GWAS
diseases
by
A signaling target of a multitude of cytokines in autoimmune diseases
(Hu et al., 2013)
Bach2
A transcriptional repressor of Blimp-1 and member of the CNC family
(Gao et al., 2015)
TRAF5 and TRAF3IP2
Members from -receptor-associated family
TNF factors
(Xiang et al., 2014)
TNIP1
TNFa-induced protein 3 interacting with protein 1, an important regulator of NF-kB activity
(Kanda et al., 2014)
STAT4
Signal transducers and activators of transcription 4, a transcript involved in T cell differentiation and T cell-mediated response
(Hu et al., 2010)
Programmed cell death 1, an immunoinhibitory receptor inhibiting lymphocyte activation
(Meng et al., 2009)
Osteopontin, a proinflammatory cytokine involved in chronic inflammatory diseases
(Chu et al., 2011)
Toll-like receptor 9, a key receptor for recognizing pathogen-associated molecular patterns from viruses
(Ito et al., 2011)
A member of receptor family
(Chen et al., 2012a)
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PDCD1
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TLR9
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JAK1
CD40
the
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MicroRNA-146a
(Zhou et al., 2012)
miR-182
MicroRNA-182, targeting the 3’ UTR of FoxO1 resulting in a decrease in Treg cells and subsequent clonal expansion of helper T cells
(Yu et al., 2014)
DHCR7, CYP2R1, CYP27B1,
Vitamin D family genes
(Fang et al., 2014)
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and CYP24A1 A susceptible locus for a large number of autoimmune diseases
(Li et al., 2015)
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CLEC16A
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Table 7.Studies on the efficacy of Infliximab on VKH disease reported previously Efficacy
2
Effective
(Khalifa et al., 2010)
2 children
Effective for one case
(Kahn et al., 2006)
2
Effective
(Niccoli et al., 2009)
2
Effective
(Suhler et al., 2009)
2
(Zmuda et al., 2013)
2
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Number (Chen et al., 2008)
helpful for one case
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